Article Type : Opinion Article
Authors : Jorge Scaglione
William Harvey was born in Folkestone, Kent, England, on April
1, 1578, and died on June 3, 1657. He was a British physician
who was credited with accurately describing, for the first time, the
circulation and properties of blood being distributed throughout
the body through the pumping of the heart. This discovery
confirmed the ideas of René Descartes, who in his book
"Description of the Human Body" had stated that arteries and
veins were tubes that carried nutrients around the body. After
receiving his medical degree in 1602, Harvey worked at the
London hospital of St. Bartholomew and became a member of the
Royal College of Physicians in 1604. He presented his circulatory
description in the second Lumleian lecture (anatomy course) on
April 17, 1616. In this lecture, he publicly presented his
revolutionary ideas about the movement of the heart and the
circulation of blood in animals. However, his magnificent
monograph "Exercitatio Anatomica de Motu Cordis et Sanguinis
in Animalibus" was not published until 1628. It has been
rightfully claimed that his great discovery was the first adequate
explanation of an organic process and the starting point of the
path that led to the field of experimental physiology. The
monograph consisted of 72 pages and included three parts: the
dedication, the prologue, and the exposition of the doctrine. It
dedicated to the King of England, was Charles I Stuart, to Dr.
Argent, the president of the Royal College of Physicians, and to
his other colleagues. The prologue is based on his personal
experimentation. The exposition of the doctrine covered 17
chapters. In the second of these, the author stated that the heart
empties when it contracts, constituting the systole corresponding
to cardiac activity, while expansion or diastole corresponded to
the filling phase. In the third chapter, he wrote that arterial diastole coincided with cardiac systole and result from the
displacement of the liquid vein sent by the heart. In the following
chapter, he note that the activity of the atria precedes that of the
ventricles and persisted after the latter's cessation. Therefore, the
atrium is the "primum movens et ultimum moriens."The "primum
movens" (in Greek: "? ?? ?????????? ?????," “What moves
without being moved ") or the first unmoved mover is a
metaphysical concept described by Aristotle as the first cause of
all movement in the universe, and therefore, it is not moved by
anything. Aristotle speaks of an immaterial being in the eighth
book of Physics, which is the physical principle of the world, and
in the Metaphysics, he referred to it as God. While our ancient
teachers were on the right path, they did not imagine the profound
scientific truth that we know today, or at least believe we know.
Scientists generally believe that the first heartbeat occurs when a
tubular structure forms in the embryo, which will eventually
become the heart. However, it is still unclear how the first
heartbeat begins and how it affects the heart's subsequent
development. Tyser, Miranda, et al [1]. Demonstrated that the
first heartbeat occurs much earlier than previously believed. In
experiments, videos of live mouse embryos showed that before
the first heartbeat, the flow of Calcium ions already exists among
different cardiomyocytes, but it is not synchronized. However, as
the heart grows, these calcium flows coordinate, and the first
heartbeat occurs, followed by subsequent beats at an initial rate of
35 beats per minute. The beats become faster as the heart grows.
Through the use of drugs that block calcium ions, Tyser and
others demonstrated that a protein called NCX1 [2]. (Which is an
essential membrane protein involved in calcium homeostasis) is
responsible for regulating calcium flows before the first heartbeat. Furthermore, the experiments revealed that these initial heartbeats
help drive the growth of cardiomyocytes and shape the
developing heart. Overall, the experiments demonstrate that the
initial heartbeats are essential for the normal development of the
heart. In the future, researchers will need to study what controls
the speed of the initial heartbeats and how calcium flows are
organized to trigger the first heartbeat. These studies may help
scientists better understand congenital heart defects and suggest
strategies for reconstructing hearts damaged by heart disease.
Once about 100 cells make up the sinoatrial node, given its
electrophysiological characteristics, they will command the heart
rate throughout an individual's life until a final beat occurs
(ultimum moriens), unless unexpected events disrupt the expected
progression.
Today, we have an-idea of when electrical activity begins to be
expressed, but the question of when and why the next beat will
occur is a matter for curious minds, which has been addressed
both before and after the discovery of the sinoatrial node (SA
node) 116 years ago [3]. The debate about the origin of heartbeats
in the mid-19th century revolved around two hypotheses: the
neurogenic theory, which posited that nerves were responsible for
the rhythmic contraction, and the myogenic theory, which argued
that a portion of cardiac muscle could beat spontaneously and
rhythmically [4]. Both hypotheses were based on studies of
bioelectricity and established a causal link between electrical
activity and muscle contraction (excitation-contraction coupling)
thanks to the invention of the galvanometer. At the end of the
century, the "membrane theory of bioelectric potentials" was
proposed to explain how cells manipulate their transmembrane
voltage (Vm), which was quantitatively demonstrated in 1912
using the Nernst equation [5]. This led Silvio Weidmann to join
the effort to solve the enigma of how changes in membrane
potential were related to contraction. In 1969, Wood, Heppner,
and Weidmann proposed possible mechanisms for the formation
of "memory" in cardiac myocytes through experiments involving
the manipulation of extracellular calcium ions [6]. They
considered the possibility that the storage and release of calcium
ions from the sarcoplasmic reticulum (SR) mediated the
amplitude of contraction in a given beat, based on patterns of
preceding beats [7]. They observed that the process of calcium
release from the SR explained how the incoming L-type calcium
current triggered the release of sufficient calcium to activate the
myofilaments. The discovery of ryanodine receptors (RyR),
calcium channels of the SR, and their antagonist, ryanodine,
improved the study of intracellular calcium flow in cardiac
myocyte contraction [8]. Finally, it was discovered that the SR of ventricular myocytes could generate spontaneous and
approximately rhythmic diastolic calcium oscillations [9]. This
led to the idea that spontaneous diastolic calcium oscillations
might be involved in the normal automaticity of the SA node
[10]. Once the first heartbeat occurs, the question is when and
why the next ones will follow. In recent experiments, it was
demonstrated that isolated SA node cells exhibit local rhythmic
releases of calcium ions from the SR (which occur independently
of changes in membrane potential). These releases are involved in
initiating the action potential by activating the sodium-calcium
exchanger (NCX), leading to membrane depolarization, which, in
turn, activates a set of ion channels in the cell membrane. Viewed
in this way, these rhythmic calcium releases form a calcium clock
that is intertwined with a membrane clock composed of surface
membrane electrogenic molecules. Together, they form a
"coupled clock" that generates spontaneous action potential
cycles in SA node cells. The automaticity of these cells is
modulated by autonomic receptors influencing both clock
molecules. For the proper functioning of these clocks, the
functionality of the hyperpolarization-activated inward current
(If), identified as the primary ionic current of SA node cells, is
critical. Its rectification inward prevents repolarization during the
membrane potential toward the theoretical electrochemical
equilibrium of potassium channels [11]. Thus, through countless
molecular interactions, the sinoatrial node sets the pace of
heartbeats for the duration of an individual's life, unless natural
aging or pathological processes lead to a final stimulus.
In 1907, Walter Karl Koch (1880–1962), a German physician
who worked in the laboratory of Aschoff, along with Tawara,
introduced the eponyms associated with this distinguished group
of researchers: the Koch's triangle [12]. Tawara's node [13]. And
Aschoff's nodule [14-15]. However, in his work titled "Über das
Ultimum moriens des menschlichen Herzens. Ein Beitrag zur
Frage des Sinusgebietes" ("On the Ultimum moriens of the
Human Heart: A Contribution to the Question of the Sinus
Area"), Koch hypothesized that the last part of the heart to lose its
rhythmic activity when dying was "its pacemaker." He conducted
experiments with deceased human and animal fetuses and located
the last part of the heart that ceased to beat as the ostium and the
wall of the coronary sinus, concluding that this location should be
considered the true pacemaker of the heart. Following the final
correction of Koch's work, Erlanger and Blackman published
their article titled "A Study of Relative Rhythmicity and
Conductivities in Various Regions of the Auricles of the
Mammalian Heart" [16]. These experiments were conducted on
the perfused rabbit heart, and their conclusions contradicted Koch's findings. They argued that the region of the right atrium
near the junction of the major veins ("sinus junctions") had the
greatest ability to maintain activity, and they believed that in
many cases, this was where the control of the heart's rhythm was
established. After learning of this work, Koch made corrections to
his initial work and wrote: "I have learned of the recent
publication by J. Erlanger and J.R. Blackman, regarding a study
of relative conductivity in various regions of the auricles of the
mammalian heart... The difference and conflict between my
observations on the dying heart and those on an artificially
exsanguinated heart can only find their solution in additional
observations, in observations in which the spatial boundaries
between the cava funnel and the coronary sinus funnel must be
more carefully considered than has been done so far." Perhaps
without human intervention, the last part to contract is the right
atrium, but starting in the 1950s with the advent of the first
implantable pacemakers and their ongoing evolution, the question
arises:
The use of implantable cardioverter-defibrillators postpones and
provides a new opportunity for the final beat to occur. The
controlled use of electricity is the responsibility of humans who
have modified the natural history of cardiac activity. As far back
as 2650 BC, there are references to the Egyptians' knowledge of
the power of certain fish, which caused painful effects on those
who touched them. This phenomenon was so well known that the
fish was attributed the ability to be a healer. For this reason, when
depicting a man who saved many lives, the Egyptians represented
him in hieroglyphics as a torpedo fish (Torpedo is a genus of
electric rays in the family Torpedinidae, popularly known as
torpedo rays. There are 22 species of torpedo rays, and they can
be found in all temperate and tropical seas around the world. Two
of them live in the Mediterranean and can generate shocks of up
to 220 volts and 1 ampere. The torpedo fish uses these organs for
hunting and self- defense). There is a representation that could
signify the treatment that an Egyptian performs on another using a
Nile catfish (electric catfish, Malapterurus electricus, belongs to
the class Actinopterygii, order Siluriformes, which includes
catfish, the electricity comes from thousands of disc-shaped
electric cells called electrocytes, closely packed and connected in
a chain to generate impulses with a voltage that can reach 350-
450 volts, depending on the fish's size) by utilizing the electric
shocks they provide. While the ancients attributed these
observations to the powers of the gods, the first observation of
electricity is attributed to the Greek philosopher Thales of Miletus
in 600 BC, who observed that dry pieces of amber could attract
small bits of dry grass after being rubbed on his robe. By 1600, William Gilbert, the president of the Royal College of Physicians,
was familiar with these magnetism experiments and studied the
effects of what he called "electricity," derived from the Greek
word "elektron" for amber. Human curiosity and experimentation
led Alessandro Giuseppe Antonio Anastasio Volta, an Italian
chemist and physicist, to develop the first battery in 1799. In a
communication to the Royal Society, Volta presented the new
device he had invented, which he called an "artificial electric
organ" because it imitated the natural electric organ of the torpedo
or electric eel. It was constructed by interleaving layers of two
metals (zinc and copper discs) placed alternately, stacked,
separated by cardboard soaked in salty water, capable of
continuously producing an electric current. This fundamental step
in energy storage eventually led to the creation of the first
implantable pacemaker in the 1950s [17-18]. From this radical
new form of treatment, technological advancements now offer us
the ability to choose different types of cardiac pacing to mimic
the so-called "physiological pacing" when possible. Not only
have devices been created to maintain cardiac stimulation, but
also for the treatment of severe arrhythmias [19]. And to assist in
the treatment of heart failure [20]. With all that science has
provided us to date, we cannot be certain where the "ultimum
moriens" occurs.