The Heart: A Biochemical and Cellular Perspective

Table of Contents


This paper focuses on the biochemical and cellular properties of different cells found in the heart tissues such as cardiomyocytes and cardiac pacemaker cells. Cardiac output is explained to demonstrate how altering certain determinants can impact the overall function of the heart due to cellular properties. Some of these properties include the automaticity and action potential of heart cells, which allow the heart to beat rhythmically. The cardiac pacemaker mechanism, also referenced as the couple-clock system, is explored to explain automaticity. Finally, different species are examined to understand why certain hearts showcase regenerative properties while others do not.

Cardiac Output

Determinants of Cardiac Output

Cardiac output is the amount of blood the heart pumps, measured in liters per minute. This value can be found using the product of the stroke volume and the number of heart beats per minute. As examined in our previous essay on mechanics, we established that the heart acts as the body’s pump, yet the amount of blood it pumps also depends on extra cardiac factors. There are four determinants of cardiac output: heart rate, contractility, preload and afterload.

To better understand, there is an analogy to be made between cardiac output and the speed of a bicycle in a given time and space (Vincent, 2008).

Heart rate

The first determinant is heart rate. The faster a heart beats, the more blood is pumped. Similarly, the faster one pedals on a bicycle, the faster it will go. This being said, if a cyclist pedals at very high speeds over a long period of time, they will face fatigue and will have to slow down, proving there is a certain limit to increasing a heart rate. For a heart rate to be maintainable, it must stay within a particular range, typically between 60 and 100 beats per minute at rest. Having an abnormal heart rate can lead to sever cardiac diseases such as bradyarrhythmia or ventricular tachycardia (Vincent, 2008).


Contractility is the second determinant and refers to the ability to self-contract. It can be compared to a cyclist flexing their leg muscles in order to push harder on the pedals and go faster. Similarly, too little contractility reduces the output and an increase in contractility leads to an increase in cardiac output, but too much effort can have the opposite effect, leading to fatigue which can cause the bicycle, or in this case the heart, to slow down significantly or even stop (Vincent, 2008).

Signaling in Muscle Contractions

Cardiac muscles are a kind of striated muscle, meaning the alternating actomyosin fibers are arranged in a way that gives the muscle a striped appearance. When there is excitation-contraction coupling, a neuronal stimulation caused by a voltage and calcium dependent process, there is rapid and coordinated contraction of the entire muscle. Contraction depends on an increase in cytosolic calcium concentration. The typical extracellular concentration of this chemical is 2 to 4 millimoles and the resting cytosolic concentration is 100 nanomoles. It is stored in the sarcoplasmic and endoplasmic reticulum, where it has a concentration of 0.4 millimoles. When the sarcoplasmic reticulum releases calcium, through ryanodine receptors, the calcium levels in the striated muscles increases. Certain neurotransmitters like acetylcholine will bind to the ryanodine receptors on the surface of the muscle in order to depolarize the calcium into sodium and calcium ions. This activates voltage gated channels, and causes action potential, also referred to as excitation. This in turn stimulates L-type calcium channels, which opens ryanodine receptors in cardiac muscles. This process is called calcium-induced calcium release.

Fig. 1 Schematic of the different steps in calcium signaling in muscle contractions. [Adapted from “Exam 3 Review:  Chapter 09:  Skeletal Muscle Cell = Fiber Histology” | APSU Biology, n.d.]

Once there is an increase in intracellular calcium levels, the calcium binds to troponin, found on actin filaments, and causes a shift in its position. This exposes myosin-binding sites to allow the formation of cross-bridges with actin, which produces the force that generates contraction (Kuo and Ehrlich, 2015).


Preload is the third determinant and is defined by the degree of myocardial distension before shortening. In order to understand how preload affects cardiac output, it is important to understand the intrinsic properties of myocardial cells demonstrated by Otto Frank and Ernest Starling.

Frank-Sterling mechanism

The Frank-Starling mechanism is a result of the length-tension relationship of striated muscles, like the cardiac muscle. As the muscle fiber is stretched, the thick and thin filaments overlap differently, which causes an active tension. The greatest active tension takes place when a muscle is stretched to its optimal length. The maximum force of a cardiac muscle is observed when a sarcomere, a unit of striated muscle, has an initial length of 2.2 micrometers. Different sarcomere lengths will have an impact on the force of the muscle. When the sarcomere is longer than this, there is less overlap between the thin and thick muscle filaments and when the sarcomere is shorter than this, the myofilaments develop a decreased sensitivity to calcium.

As the ventricle fills, the cardiac muscle is stretched and the filaments get closer to their optimal length, which increases the strength of the muscle for many reasons. For this reason, the force generated by cardiac muscle fibers is related to the end-diastolic volume of the ventricles. The stretch of cardiac muscles decreases the space between filaments, which increases the number of cross-bridges formed. Stretching these muscle fibers also increases their calcium sensitivity, which leads to an increase in actin-myosin cross-bridges, producing force. The sensitivity of troponin, a protein that regulates muscular contraction, that binds to calcium ions (Ca2+) increases and there are more calcium ions released from the sarcoplasmic reticulum, a membrane bound structure in muscles. The force generated by a cardiac muscle fiber is directly related to the length of the sarcomere when the muscle cells are activated by calcium (Allen and Kentish, 1985).

Fig. 2 The relationship between ventricular end-diastolic volume, i.e., the amount the ventricular muscles are stretched, and the ventricular performance related to cardiac output. [Adapted from Liu, 2020]

If we compare preload to the bicycle analogy, it can be viewed as being a tailwind that allows the bicycle to be faster without using more muscular effort. The only difference would be that a preload value will eventually reach a maximum value that can no longer increase the cardiac output (Vincent, 2008).


Afterload is the fourth and final determinant of cardiac output. It refers to the force that ventricles must exceed to eject blood. It is largely influenced by arterial blood pressure and vascular tone. Reducing afterload increases cardiac output, particularly when contractility is impaired. Comparatively, a cyclist navigating through a narrow road with obstacles will travel at a slower speed than a cyclist on a clear and large circuit (Vincent, 2008).

Sufficiency and Efficiency of CO

The cardiac output of a healthy heart at rest varies between 5 and 6 liters of blood every minute. However, it is possible for a heart rate to increases during exercise or a period of stress. For example, cardiac output increases during exercise both by increases the volume of blood that fills the left ventricle and by pumping with more force (Healthwise Staff, “Cardiac Output”). Cardiac output can increase when any of the four determinants vary. This can be summarized by the following relation:

\uarr cardiac \space output = \uarr heart \space rate \space OR \space \uarr preload \space OR \space \darr afterload


It is important for a cardiac output to be sufficient to maintain a sufficient oxygen supply to the organs in the body. Efficiency is defined as the ratio of external work with respects to oxygen consumption. Cardiac efficiency, for example, is usually between 20 and 25 %. The myocardial conversion efficiency is defined as the pressure-volume area divided by the total oxygen consumption per beat:

Myocardial \space conversion \space efficiency = {PVA\over total \space V_{O_2}} 


This efficiency fluctuates between 40 and 50 % (Westerhof, 2000).

Cardiomyocytes and the Cardiac Pacemaker Cells

The heart consists of two types of cells: cardiomyocytes and the cardiac pacemaker cells. The cardiomyocytes make up most of the heart tissue including the atria and ventricle. These cells are essential in the operation of heart contraction and relaxation (Boyett et al., 2000). Every cardiomyocyte is made of myofibers consisting of a long chain of sarcomeres, which was elaborated in the architecture section of “The Heart: A Mechanical Perspective” (Dickman et al., 2020).

The other type of cell maintains the consistent operation of the heart and satisfies the property of rhythmic beating. The pacemaker cells form a Sinoatrial (SA) Node, located in the superior and posterior walls of the right atrium near the orifice of the superior vena cava (Hill, 2018). Within the intercaval region, the SA node may occupy the entire thickness between the endocardium and epicardium as in the rabbit, guinea pig and monkey. However, in the human, dog and pig there is a layer of atrial muscle between the SA node and endocardium. The atrial muscle in the intercaval region together with extensive connective tissue is thought to protect the region against the high wall stresses.

There are two main characteristic features for SA node: firstly, the SA node is composed of three main parts: the connective tissue, collagen and fibroblast. Second, a high density of nuclei has been found in SA node, meaning the SA node cells are relatively small compared to atrial cells (Pinnell et al., 2007). In fact, the SA node is reported to be 5–10 μm in diameter in the human and dog, 25–30 μm long and < 8 μm in diameter in the rabbit, whereas atrial cells in these species are approximately 100 μm in length and 15–20 μm in diameter (Boyett et al., 2000).

Another interesting fact about the SA node cells in some animals is their “emptiness”, which suggests they contain only a few poorly organized myofilaments, which run in all directions and are not organized into myofibrils.

Fig. 3 Specialized conducting components of the heart include the sinoatrial node, the internodal pathways, the atrioventricular node, the atrioventricular bundle, the right and left bundle branches, and the Purkinje fibers. [Adapted from Betts et al., “Cardiac Cycle”]

Action potentials and Automaticity

As discussed above, the self-contraction and relaxation is controlled by the SA node. Such a control is accomplished by the action potential passed between cardiac cells, which is a sudden, fast, transitory, and propagating change of the resting membrane potential. Only neurons and muscle cells can generate an action potential; that property is called the excitability (Ikonnikov and Yelle, n.d.). In general, stimuli will cause a temporary change in the membrane permeability, leading to the opening of ion channels and thus a decrease in ionic concentration gradient.

There are two main factors that influence the ion movement across the membrane: chemical potential and electrical potential, meaning ions will move along the concentration gradient and away from the like charges. These moving ions determine the transmembrane potential (TMP), the magnitude of which may trigger an action potential and then a cardiac contraction (Pinnell et al., 2007). The action potential of most cardiomyocytes consists of 5 phases: The resting phase (phase 4), depolarization (phase 0), early repolarization (phase 1), the plateau phase (phase 2), and repolarization (phase 3). Each of these phases corresponds to the opening or closure of specific ion channels (Hill, 2018).

Fig. 4 The action potential of cardiac muscles. Illustrated by Grigoriy Ikonnikov and Eric Wong. [Adapted from Ikonnikov and Wong in 2013]

However, the other type of heart cell, the pacemaker cell, has different potential phases. Compared to normal cardiomyocytes, it lacks the phase 1 and 2 and occurs continuously at the end of a previous action potential. This appearance of action potential also suggests the very important feature of pacemaker cell: automaticity. The pacemaker cells do not need any external stimuli to initiate an action potential as they have a spontaneous depolarization mechanism (Hill, 2018).

Fig. 5 The action potential of pacemaker cells. [Adapted from Ikonnikov and Yelle, n.d.]

The SA nodes and AV nodes have inherent pacemaker activity. An AV node is a structure located between the left and right atrium, where the signal is delayed about 0.1 second before reaching the heart apex. Such a delay makes sure the atria are completely empty before further processing the cardiac cycle. The SA node has the highest rate of spontaneous depolarization and therefore suppresses the other pacemakers. In the denervated heart, the SA node discharges at a rate of approximately 100 times/min. Vagal tone, activity under the vagal nerve, which is not under conscious control, leads to a lower heart rate in healthy subjects at rest. From the SA node, impulses spread throughout the atria to the AV node at a rate of 1 m/s. The AV node is the only means of electrical connection between the atria and the ventricles. Conduction here is slow (approximately 0.05 m/s) (Boyett et al., 2000).

Cardiac function relies on the timing at which excitation and contraction occur in the heart as well as a stable and constant pacemaker rate. This function is fulfilled by many elements, including the sinoatrial node (SAN), the atria, the ventricles and the atrioventricular node (AVN). These several regions of the heart contain many ion channels at the center of molecular mechanisms which underlie cardiac automaticity. The anatomical design and structure of the heart (ventricular network, SAN, pacemaker structure) was determined over a century ago, however, the molecular and cellular mechanisms of pacemaker firing are yet to be fully understood (Weisbrod et al., 2016). In fact, the understanding of cardiac pacemakers and their activity within the heart continues to evolve even today (Maltsev et al., 2014). Many scientists disagreed on the origin of pacemaker cell function and whether it originated from intracellular or cell membrane processes. As a result, many hypotheses were made in order to explain automaticity of SAN cells. A more recent theory demonstrated that both intracellular and cell membrane mechanisms work in a coordinated and concomitant manner (Maltsev et al., 2014) to achieve this.  

Diastolic Depolarization

First, we can define the pacemaker activity of a cell as its “ability to spontaneously and cyclically generate an electrical signal” (Weisbrod et al., 2016). In order to do so, the membrane potential of a SAN cell must depolarize to reach a certain threshold which in turn generates an Action Potential (AP). We call this depolarization ‘Diastolic Depolarization’ (DD); it transpires at the end of an AP during diastole and stimulates the next action potential (Weisbrod et al., 2016). The pacemaker cells create rhythmic changes spontaneously, starting with slow DD from the maximum diastolic potential at –60 mV. When the membrane potential (Vm) reaches a threshold of – 40 mV, which we call “excitation”, the pacemaker cells generate new action potentials (Maltsev et al., 2019). In comparison, myocytes sustain a resting potential between – 80mV to – 90mV. This value is close to the potassium (K+) equilibrium potential (Maltsev et al., 2014), which is due to an inward-rectifier potassium current (Husse and Franz, 2016). DD is the main reason as to why the heart can beat in a spontaneous manner. Inward currents at diastolic potentials and sarcolemmal ion channels are at the core of automaticity (Weisbrod et al., 2016). 

The Cardiac Pacemaker Mechanism: A Coupled-Clock System

DD occurs in a continuous manner as a result of voltage-sensitive membrane ion channels in SAN cells. Automaticity of these sinus node cells can be explained by two interacting phenomena forming a coupled-clock mechanism known as the “membrane clock” and the “Ca2+ clock” (Husse and Franz, 2016). Specific processes occurring in the membrane clock are the basis of pacemaker activity and rely on membrane ion channel activity. The Ca2+ clock represents the effects of intracellular Ca2+ on spontaneous activity of pacemaker cells (Husse and Franz, 2016). Together, this system of intracellular and cell membrane elements produces intracellular Ca2+ and electrical signals necessary for pacemaker function (Maltsev et al., 2014).

Fig. 6 Coupling of the membrane-clock and calcium-clock in SAN cells. [Adapted from Husse and Franz, 2016]

Membrane Clock

Electrogenic proteins and molecules such as voltage-sensitive ion channels and transporters contained inside the cell membrane have an important impact on the generation of APs by pacemaker cells. The Hodgkin-Huxley (H-H) gating mechanism describes activation and inactivation kinetics of cell membrane ion channels who are themselves able to cause pacemaker potentials (Maltsev et al., 2014) by depolarizing the membrane until it reaches a threshold which triggers an AP (Husse and Franz, 2016), as previously mentioned. The ensemble of ion currents produced by these sarcolemmal molecules forms a sort of ‘voltage membrane oscillator’, which we call membrane clock or M-clock (Maltsev et al., 2019). Some important membrane clock elements are the hyperpolarization-activated funny current (If), T-type Ca2+ current (ICaT), L-type Ca2+ current (ICaL), sodium-calcium-exchanger (NCX), delayed rectifier potassium currents (IK), and a sustained inward current (Ist) (Maltsev et al., 2014).

Funny current (If)

At the beginning of diastolic depolarization, hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), also called ‘funny currents’ (If) are triggered when the threshold reaches – 50 to – 65 mV. The role of these channels in the generation of APs was researched in several studies with the use of SAN cells (Husse and Franz, 2016). When HCN channels were suppressed, the heart rate underwent a 3 to 24 % decrease. This observation suggests that HCN channels are not the sole mechanism responsible for controlling spontaneous APs. However, a mutation in one of the four genes that encode funny channels (HCN4) engenders arrhythmia. This demonstrates the significance of HCN channels in the regulation of pacemaker activity (Husse and Franz, 2016).

Ca2+ currents

Other important mechanisms that occur in SAN cells are Ca2+ currents. The core of these mechanisms lies behind activity in voltage sensitive T-type Ca2+ (ICaT) and L-type Ca2+ (ICaL) channels. To demonstrate the importance of ICaT channels in AP generation and spontaneous depolarization, we can suppress these channels by inhibition with Ni2+. This resulted in a 10 % decrease of heart rate (Husse and Franz, 2016). Among mammals, ICaT channels have a different contribution to depolarization which is dependent on animal size. For instance, mouse SAN cells contain a considerable amount of ICaT; however, this amount is less significant in larger animals like rabbits and guinea pigs and almost inexistant in pig SAN cells. Furthermore, ICaL channels are at the origin of AP upstroke and are the most important for generating APs in SAN cells (Husse and Franz, 2016).

Sodium-Calcium-Exchanger (NCX)

The electrogenic Na+/Ca2+ exchanger (NCX) plays a major role in the late phase of diastolic depolarization (Husse and Franz, 2016). It also influences heart contractility, which will be further explained in the cardiac output section, as it regulates Ca2+ efflux within cardiac myocytes (Ottolia et al., 2013). NCX can also reverse current flow during APs. Ca2+ is an important component in cardiac activity, this is why its concentration within cardiac cells must be carefully monitored, hence the presence of a sodium-calcium-exchanger (Bers, 2002). Between APs (i.e., when no action potentials are triggered), NCX uses the large concentration of extracellular Na+ to its advantage and sends Ca2+ outside the cell. However, during upstroke of the AP, a stream of Na+ flows in, resulting in the depolarization of the cell and increase of the concentration of Na+ ions inside the cell. This induces a short reversed NCX action which pumps Na+ outside the cell and Ca2+ inside. This reversed action only lasts for a brief moment as the influx of Ca2+ into the cell allows NCX to go back to its usual flow direction looking for balance by ejecting Ca2+ to the outside of the cell (Yu and Choi, 2006).

Fig. 7 SAN cell action potential and substantial currents involved in the early and late components of diastolic depolarization. [Adapted from Husse and Franz, 2016]

Calcium Clock

Fig. 8 Operation of the calcium clock in SAN cells. [Adapted from Logantha et al., 2016]

An important intracellular pacemaker mechanism is the calcium clock, linked to the sarcoplasmic reticulum (SR) which stores Ca2+ in cardiac cells (Maltsev et al., 2014). It works as a Ca2+ capacitor. The SR releases intracellular Ca2+ which is partially responsible for the automaticity of SAN cells, influencing heart rate (Husse and Franz, 2016). It has Ca2+ release channels (ryanodine receptors, RyRs) which liberate Ca2+ underneath the cell membrane, and a Ca2+ pump (SERCA) which regulates Ca2+ concentration (Tsutsui et al., 2018). The sarcoplasmic reticulum can produce rhythmic Ca2+ oscillations at specific time intervals, independently from cell membrane function (membrane clock) (Maltsev et al., 2014). During the late phase of DD, local Ca2+ release (LCR) is generated by the calcium clock, which stimulates NCX (Husse and Franz, 2016). LCRs occur underneath the cell membrane during which RyRs are activated (Maltsev et al., 2014).

Clock Coupling

Membrane clock and calcium clock both regulate membrane potential and intracellular Ca2+, either in a direct or indirect manner. Therefore, they do not act independently of one another but more as a ‘bidirectionally coupled system’ (Tsutsui et al., 2018). Ca2+ —cAMP (Ca2+–adenosine 3′,5′-monophosphate) — protein kinase A (PKA) signaling, inherent to SAN cells, regulates clock coupling (Tsutsui et al., 2018).

The level of clock coupling is not constant and varies over time. If the clocks were to become uncoupled, which can happen naturally without being forcefully induced, SAN cells would be unable to produce APs since the Ca2+ releases would fail to trigger membrane clock processes. However, it is possible to recouple both clocks and reactivate spontaneous AP firing by β–AR stimulation–induced augmentation of Ca2+-cAMP-PKA signaling (Tsutsui et al., 2018).

Fig. 9 The timing of membrane and calcium clock mechanisms during SAN action potentials. [Adapted from Vallejo-Vaz, 2015]

Regenerative Properties of the Heart

As we have now fully examined the cellular and chemical functioning of the mammalian heart under normal circumstances, let us look at the heart’s response to trauma. Mammals are incapable of regenerating muscle cells of the heart (de Wit et al., 2020). Instead, dead cells are replaced by fibrotic tissue which, possessing different mechanical properties than cardiomyocytes, engender numerous problems such as decreased cardiac output and arrythmia (Richardson et al., 2015). On the other hand, lower order vertebrates such as the zebrafish and newts have the remarkable ability of completely repairing their heart within a few months (de Wit et al., 2020).

As more research has been done on the zebrafish than on the newt, this section will focus on the zebrafish.

Fig. 10 Zebrafish. Photographed by Lynn Ketchum. [Adapted from “Zebrafish” | Oregon State University’s Flickr profile, 2013]

At the Heart of the Zebrafish

The zebrafish can completely recover from an injury which damaged up to 20 % of its ventricle within a month or two, with the heart fully regaining its pre-injury efficiency and function (de Wit et al., 2020).  

The wall of the heart is composed of three layers. The endocardium (EC), the myocardium and the pericardium (EP) (González‐Rosa et al., 2017). The myocardium is itself composed of three layers: the trabecular myocardium, the primordial myocardium, and the cortical myocardium (González‐Rosa et al., 2017). Like mammalian hearts, the cortical myocardium contains complex vasculature (de Wit et al., 2020). Unlike mammalian hearts, however, zebrafish cardiomyocytes are mononucleated, diploid and retain the capability of proliferating during the entirety of the zebrafish’s lifetime (de Wit et al., 2020). This capability of reentering the cell-cycle forms the basis of the regeneration of the heart.

Fig. 11 Wall of a zebrafish heart. [Adapted from González‐Rosa et al., 2017]


General Overview

A fibrotic clot immediately forms at the injury site to prevent excessive blood loss (González‐Rosa et al., 2017). This is followed by an inflammatory phase where dead cells are cleared out and the wound is stabilized by the extracellular matrix (González‐Rosa et al., 2017). Then, the cells in undamaged parts start to dedifferentiate and proliferate, migrating towards the injured area where vasculature is rebuilt (González‐Rosa et al., 2017). This results in the complete recovery of the heart.  

Two hypotheses were proposed to explain the origin of these new cardiomyocytes. On one hand, they could be the result of stem cells. In this case, similarly to what occurs during embryonic heart development, undifferentiated cells from the mesoderm would acquire cardiac characteristics and form the heart while epicardium cells will differentiate and enter the myocardium to form vasculature (Engel, 2012). This process is called the epithelial-to-mesenchymal transition (Engel, 2012). On the other hand, new cardiomyocytes could be the result of undamaged cells dedifferentiating and re-entering the cell cycle, allowing them to replicate and then differentiate into cardiomyocytes (Engel, 2012). Recent studies tend to prove the validity of the latter process although some suggest that both occur simultaneously (Vivien et al., 2016).


Dedifferentiation of a cell is the process through which a cell loses its specialized features and returns to a more basic state, allowing it to re-enter the cell cycle and proliferate (Cai et al., 2007). As they dedifferentiate, the sarcomeres forming the cardiomyocytes lose their structure, contractility decreases, and embryonic genes are expressed (de Wit et al., 2020). This process is onset by many different elements such as hypoxia (low levels of oxygen) which suppresses contractility genes and enhances cell cycle genes (de Wit et al., 2020). The mechanical properties of the extracellular matrix play a fundamental role too. In mice, rigid ECM causes the nucleus to divide while the cells remain intact whereas elastic ECM causes dedifferentiation of the cell (de Wit et al., 2020). Furthermore, mice gain cardiac regenerative ability when they are injected with zebrafish ECM, demonstrating potential clinical applications in the treatment of myocardial infarctions in humans (de Wit et al., 2020).  

Proliferation and Revascularization

Four types of proteins can stimulate the cell cycle: growth factors, growth factor receptors, signal transducers and transition factors (Editors of Encyclopedia Britannica, “Cell cycle”). Accordingly, these are secreted after injury (Vivien et al., 2016). The endocardium produces Radlh2 which forms retinoic acid from vitamin A (de Wit et al., 2020). Retinoic acid is a growth factor which stimulates cardiomyocyte proliferation (de Wit et al., 2020).  The epicardium, on the other hand, produces gata4, a transcription factor (González‐Rosa et al., 2017). Many other factors contribute too, such as nerves and miRNA (González‐Rosa et al., 2017). The epicardium, on the other hand, is responsible for revascularization of the injury site in a process that is reminiscent of the epithelial-to-mesenchymal transition occurring during embryogenesis (González‐Rosa et al., 2017). Fibroblasts produce Fgf ligands while epicardial cells contain Fgf receptors, thereby attracting epicardial cells towards cardiac muscles where they will form the vasculature (de Wit et al., 2020).

Migration and Redifferentiation

The site of injury expresses Cxcl12a ligand while epicardial cardiomyocytes express its receptor, Cxcr4b (de Wit et al., 2020). Consequently, epicardial cardiomyocytes migrate towards the injury site. Finally, cells re-differentiate to gain properties necessary for the efficient functioning of the heart such as the ability to contract as well as electric coupling (de Wit et al., 2020).


Interestingly, it is not known what evolutionary process caused some animals to be able to regenerate their hearts while others cannot. Indeed, while many fishes and amphibians have great regenerative capabilities, no adult mammals can regrow their heart (Vivien et al., 2016). Although more research is needed, it is thought that mammals have sacrificed their regenerative abilities for a stronger heart as high blood pressure is thought to impede regeneration (Vivien et al., 2016). Similarly, there seems to be a tradeoff between a complex immune system and regeneration as newts do not have an adaptive immune system but can regrow limbs and organs while mammals have a developed immune system but have very limited regenerative capabilities (Vivien et al., 2016).

Wood Frog

While the zebrafish’s ability to recover from injury inflicted upon its heart is remarkable, another animal has a mechanism in place to prevent injury: the wood frog produces antifreeze to prevent cryoinjuries (Layne and Lee, 1995).

Fig. 14 The Wood Frog. Photographed by Dave Huth. [Adapted from Dave Huth’s Flickr profile, 2011]

Wood frogs are able of producing their own antifreeze which prevents their cells from being dehydrated and shriveled up by the formation of ice (Layne and Lee, 1995). In preparation for the winter, frogs will store large amounts of glycerol in their liver which will be converted into glucose (Layne and Lee, 1995). This will help maintain the cells’ shape and reduce dehydration (“Frogsicles: Frozen But Still Alive” | Smithsonian Channel | YouTube, 2015). As ice settles in, the heart will continue to beat just long enough to distribute glucose to vital organs before shutting down (Layne and Lee, 1995). Consequently, this antifreeze protects the cells and allows the heart to remain intact while the frog is frozen solid, thereby allowing it to start pumping again as the frog thaws in spring (Layne and Lee, 1995).   


In this paper, we have examined the cellular and chemical components involved in the control of cardiac output and maintenance of the heart’s beating rhythm as well as its regeneration in some species. 

Cardiac output relies upon four determinants, particularly contractility, which depends on the calcium signaling in cardiac muscles, and preload, which depends on the Frank-Sterling relation between stretch of the muscle and generated power.

The specialization of SA node cells has made the automaticity of heart contraction possible by conducting electrical signals to coordinate all other cardiomyocytes, which possess a normal 5-phases action potential. On the contrary, the 3-phases action potential creates the pacemaker cells’ spontaneity.

Through the process of diastolic depolarization, action potentials are fired from within the sinoatrial node cells. During this process, many electrogenic mechanisms and ionic currents occur in two separate, but coordinated mechanisms: the membrane and calcium clocks. When coupled, they allow for a spontaneous AP to be fired, thus sustaining the function of automaticity.

We conclude this paper by examining two animals with exceptional features. We start by diving into the heart of the zebrafish and its remarkable regenerative capability enabled by the re-entry of its healthy heart cells into the cell-cycle. We then hop on to the wood frog and its ability to come back to life after being completely frozen.


“Frogsicles: Frozen But Still Alive.”, 19 June 2015, Smithsonian Channel, YouTube,


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