DOI: 10.5958/2319-5886.2015.00077.

International Journal of Medical Research

&
Health Sciences

www.ijmrhs.com
Volume 4 Issue 2
Coden: IJMRHS
th
Received: 20 Jan 2015
Revised: 28th Feb 2015
Review article

Copyright @2015 ISSN: 2319-5886

Accepted: 19th Mar 2015

EVOLUTION OF AUTOMATICITY OF HEART PACEMAKER STUDIED FROM A THEORETICAL

PERSPECTIVE
3

Vijay Kumar Konuri1, Mohammed Abdul Hannan Hazari2, Ravi Kumar K , Chandrasekhar M ,
5

Ambareesha K , Ram Reddy B

1

Associate Professor, Department of Anatomy, All India Institute of Medical Sciences, Raipur, Chhattisgarh,
India
2
Associate Professor, Department of Physiology, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad,
Telangana, India
3

Assistant Professor of Anatomy, Govt Medical College, Jagdalpur, Chhattisgarh

Professor and HOD, 5Tutor, Department of Physiology, Meenakshi Medical College, Kanchipuram,
Tamil Nadu
4

Professor & HOD, Department of Physiology, Apollo Institute of Medical Sciences and Research, Jubilee Hills,
Hyderabad, Telangana, India.
*Corresponding author email: [email protected]
ABSTRACT
The pacemaker of the mammalian heart had developed a robust and yet a flexible system in the course of
evolution whose function is based on multiple interactions at the sub-cellular, cellular and finally at the tissue
level. These, in turn, should respond to extrinsic signals. Cardiac action potentials were explained for a long time
based on the changes that occur at the cell surface. New hypothesis was put forward at the turn of the century that
pointed to the role of intracellular calcium clock. Discovery of ryanodine receptors, fluorescence labeling
techniques, confocal imaging and finally computer modeling of physiological processes had brought about a
noticeable change that allowed development of a new concept of pacemaker automaticity. Reviewing all these
developments we hereby put forward a few theoretical formulations that can turn out to be new instruments in
advancing our knowledge of cardiac physiology. We had theorized that cardiac muscle is an emergent property of
smooth muscle in the course of evolution, and that pacemaker activity of the cardiac muscle underwent a phase
transition that finally led to the evolution of a structural pacemaker.
Keywords: Heart, Pacemaker, Automaticity, Evolution
INTRODUCTION
The sino-atrial node (SAN) pacemaker cells produce
billions of incessant and uninterrupted beats in the
course of the life time of an individual. It is evident
that the pacemaker of the mammalian heart has
developed a robust and yet a flexible system in the
course of evolution [1]. Robustness indicates the failsafe properties and flexibility signifies the
adaptability to changes in the demands made on it.
The pacemaker function is based on multiple

interactions at the level of sub-cellular, cellular and

finally at the level of tissue architecture, which in turn
should react to extrinsic signals like stretch, electrical
and chemical signals that act on the cell surface
receptors.
The generation of action potentials in the
myocardium was explained for a long time,
predominantly, basing on the changes that occur on
the cell surface and its ion channels [2]. However, the

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turn of the century has brought new evidence pointing

to the role of an intracellular clock. This turned out to
be the cyclical rhythm of cytosolic Ca2+
concentration. Sarcoplasmic reticulum (SR) has
proved to be having the capacity to operate another
physiologic clock of calcium cycles[3]. Recent
developments in experimentation like confocal
imaging have revealed the presence of multiple
spontaneous, rhythmic, local calcium releases[4].
These tightly regulated processes begin to occur
beneath the cell surface during the later part of
diastolic depolarization. This activates the Na+-Ca2+
exchanger that causes an explosive increase in
diastolic depolarization and leads to the activation of
L-type calcium channels[5].

Fig 1. Interplay between intracellular and membrane

surface Ca2+ clock.
The existing understanding of cardiac action
potentials
The explanation of action potentials in the working
myocardium is as follows. Phase 0 or the rapid
depolarization results from the opening of the fast
Na+ channels. Phase 1 of the action potential starts
the repolarization process and is attributed to the
closing of Na+ channels and inward movement of Clions. Phase 2, the so-called "plateau" phase of the
action potential results from several mechanisms but
could be mainly because of slow inward movement of
Ca2+ and Na+. Phase 3 involves relative rapid
repolarization, commencing with inactivation of slow
Ca2+ and Na+ channels and rapid outward movement
of K+ ions. Phase 4 restores the ionic composition
back to the resting state by Na+-K+ ATPase which
pump Na+ ions out and K+ ions inside the cell[6].
Membrane
potential
of
pacemaker
cells
spontaneously declines to the firing level and is
known as prepotential or pacemaker potential which

triggers the next action potential. At the peak of each

action potential, conductance of potassium (IK+)
begins and repolarization occurs. IK+ then declines
and the membrane potential reaches slight
hyperpolarization. At this instance an "h" or "f"
channel which allows both Na+ and K+ is activated.
As conductance through "h" channel (Ih) increases,
the membrane begins to depolarize forming the initial
part of the prepotential. T-type Ca2+ channels then
open and its conductance (ICa2+T) completes the
prepotential. At this juncture L-type Ca2+ channels
open and ICa2+L produce action potential.
The measurements of calcium concentrations
The finding that oscillations in Ca2+ concentrations
were inhibited by calcium channel blockers (CCBs)
had brought to the fore the idea that Ca2+
concentration represents a two-way interaction
between the intracellular Ca2+ stores and the
membrane surface potential changes[7]. But due to the
rapidity of changes; spontaneous, localized
oscillations of the calcium clock could not be
measured within the individual SA nodal cells and
hence the concept that initiators of the normal
automaticity of pacemaker cells are internal calcium
oscillations could not be established.
The membrane surface processes was disconnected
from that of intracellular oscillations, for a long time,
by the employment of Ca2+ overload conditions to
voltage clamp studies[8]. Studies have gradually
demonstrated that the intracellular oscillations could,
in fact, produce spontaneous membrane currents. It is
now considered that the intracellular oscillations
involve the cycling of Ca2+ ions between SR and
cytosol[9].
Discovery of ryanodine receptors
Then came the discovery that the drug named
ryanodine can have a profound negative chronotropic
effect on the automaticity of cardiac pacemaker cells.
By studying the effect of ryanodine on the contour of
the action potential it was suggested that Ca2+
released from the SR contributes to diastolic
depolarization[10].
It is now possible to measure the intracellular calcium
levels in spontaneously firing pacemaker cells of
SAN which made it clear that each spontaneous
action potential evokes a calcium gradient in the
cytosol and that the influx of calcium through L-type
calcium channels affects the calcium loading of the

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SR. Intracellular buffering of calcium has the potency

to block the generation of spontaneous action
potentials[11]. This constitutes a strong evidence in
favor of the idea that normal automaticity of
pacemaker cells is strongly linked with the dynamics
of intracellular calcium.
Modern techniques
Fluorescence imaging of intracellular calcium is
made possible in the last decade that enabled to
document not only the global transients of cytosolic
calcium but also of many localized calcium releases
beneath the cell surface during late diastolic
depolarization[12]. Such local calcium releases are
observed in SA nodal cells in the absence of changes
in the membrane potentials, i.e. in voltage clamped
SA node pacemaker cells. There is evidence that local
Ca2+ release from the sarcoplasmic reticulation (Ca2+
sparks) occurs during the prepotential. Local calcium
releases (LCRs) during the late diastolic
depolarization begin to boil and then explode into an
action potential[13].
A tiny change in the current to the degree of 3 pA is
enough to explode into an action potential during the
critical diastolic depolarization phase of rabbit SA
node cells. Although the individual local release of
calcium during the diastolic depolarization of
pacemaker cells is relatively small and stochastic in
nature, the synchronized and cumulative effects of
LCRs imparts and impacts the rising phase of
diastolic depolarization leading to the next action
potential. A failure to generate an exponential phase
in diastolic depolarization is the consequence of a
failure to generate diastolic INCX[14].

Structurally SA node is heterogeneous

Till now we discussed the mechanisms of
automaticity and spontaneous calcium cycles in
individual pacemaker cells. But cardiac pacemaker
function cannot be understood completely by the
study of the intrinsic properties of the pacemaker
cells. Advanced histological studies had revealed that
SA node is a highly heterogeneous structure with
small pacemaker cells predominantly located in the
centre[15]. The SA nodal tissue is characterized by
complex cell-to-cell interactions in generating the
highly robust impulses with a fail-safe mechanism[16].
The function of the pacemaker tissue within the SA
node is determined by the intrinsic properties of
individual cells that are being modulated by several
factors of the local environment within the SA
node[17]. The pacemaker tissue is at the same time
being influenced by extrinsic modulators that include
the electrical and mechanical forces as well as the
autonomic milieu. These modulatory factors are
heterogeneous throughout the SA node which could
explain the differences in the shape of the action
potential curves of different cells in the same
locality[18]. This could be the result of mutual
interaction between the depolarizing charges
generated by individual SA node cells and the
structural properties of the surrounding non-excitable
tissue[19].
Extensive amounts of connective tissue and numerous
fibroblasts occupy from 25% to almost 90% of the
area of SA node[20].

Fig 2: Phase transition and emergence of cardiac muscle from smooth muscle with maintenance of legacy
in some aspects

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In addition to bands of connective tissue, the gap

junction proteins are also found to be located in
various types and with varying densities in near
vicinities. The myofilament density decreases from
periphery to the centre of the SA node[21]. The nerve
endings and autonomic receptors on pacemaker cells
are found to be at the highest density in the central
area of SA node[22]. All these structural features make
the SA node a highly heterogeneous structure that can
generate not only flexible but also a robust action
potential[23].Intracellular calcium cycling plays a
major role in the generation of automaticity in
embryonic cardio myocytes and so could be used to
generate stem cell derived spontaneously beating
myoblast cells[24].
Discussion: A theoretical approach is needed to
interpret physiology at an advanced level
We have seen how our concepts of pacemaker
potentials transformed over time, from the more or
less simplified notions that membrane currents
explain everything to developing a more and more
complex picture of mutual entrainment of the
cytosolic and the membrane clocks and of their
different mechanisms in generating automaticity.
We understand the vertebrate circulatory system as a
closed canal system comprised of network of smooth
muscle and other cells, the proximal part of which
has been transformed into cardiac muscle due to
increased circulatory load imposed on the
system[25].This can be visualized as a type of phase
transition during evolution of smooth muscle there by
transforming phase maker activity from a network of
molecules to a network of cells and tissues, which can
justify the existence of special conducting system in
myocardium. So this can be generalized as an
emergent property of smooth muscle. Pacemaker
properties of the smooth muscle is well preserved
but is now regulated by pacemaker system of cardiac
muscle. Even in smooth muscle the initiation of
pacemaker activity is due to the oscillations of
intracellular calcium that are being modulated by
external conditions. It is our endeavor to elucidate
how function is translated into structure through the
alteration of the genetic program.
CONCLUSION

Pacemaker in mammalian heart is the phase shift

transformation of the smooth muscle through cardiac
muscle during the evolutionary process. In the course
of development of highly evolved forms of
organisms, the metabolic necessities of the complex
tissues and organs demanded continuous supply of
nutrients and gases for sustenance of life. Hence, the
smooth muscle underwent structural and functional
adaptations to develop into cardiac muscle which
further acquired autonomy at the expense of losing
the contractility to form pacemaker tissue. This aptly
describes the proverb "Necessity is the mother of
invention".
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