Certain ions, ion currents over both sides of the myocardial cell membrane and the cell membrane itself (including its integral structures like membrane channels, receptors, and enzymes), and, also, a number of internal cell structures work together to produce the electrical activity of myocardial cells. Electrical activity achieved as a result of different ion currents (Na⁺, K⁺, and Ca²⁺) and activation of certain receptors or enzymes can alter this activity. In fact, the ion currents have the main role, and other factors like sympathetic and parasympathetic effects do not exert roles in generation of action potential; if we denervate the heart of an animal in lab, action potential and impulse generation would not be stopped but can affect the generation and shape of the action potentials.

Generation of action potential is essential for producing mechanical activity in the muscular wall of atria and ventricles, depolarization for contraction and repolarization for relaxation. For this, the action of the heart is called electromechanical activity.

Generally, there are two types of action potential in the heart: fast response action potential in the myocardium and Purkinje system and slow response action potential in nodal cells. Myocardial action potential consists of five sequential phases: phase 0 to phase 4. These phases compose together the electrical wave of myocardial cells known as action potential, “AP”, which are described here in Table 3.1 and Fig. 3.3.

How does the pacemaker activity in the cardiac cells happens? For answering this question, we should look for the main difference between “myocardial cells” and “pacemaker cells” regarding action potential.

There is another important concept in action potential of many cells including myocardial cells and that is “refractory period” which is the time interval during which there is no response to new impulse or the response could be sluggish: absolute refractory period or relative refractory period, respectively. Though described as one of the basic properties of currents alongside the cell membrane, some studies strongly believe that post-repolarization refractoriness plays a protective role against “reentrant” mechanisms of arrhythmias, especially in preventing atrial fibrillation.

In all cells having refractory period, the time interval for refractoriness is proportional to the time duration of action potential, and it is primarily dependent on the duration of phase 2 “plateau,” so:

What is the underlying mechanism for automaticity of pacemaker cells? Three theories are proposed: M-clock theory, Ca ²⁺ clock theory, and coupled clock theory, described here in brief:

Calcium homeostasis should be discussed at first since Ca²⁺ homeostasis has a central role in ECC. As a matter of fact, Ca²⁺ homeostasis is one of the most important cellular processes in all cells including myocardial cells. Intracellular Ca²⁺ is not only a second messenger, but in myocytes, it has other roles; the dual-phase pattern of Ca ²⁺ cycling (i.e., Ca²⁺ release and Ca²⁺ reuptake) is the basis for lifelong contraction and relaxation of the heart; needless to say, many intracellular proteins are involved in Ca²⁺ homeostasis; on the other hand, many intracellular interactions of the heart are dependent on Ca²⁺ homeostasis, including:

The sarcoplasmic reticulum (SR) is the main source of intracellular Ca²⁺ storage; however, in “pediatric heart” the amount of Ca²⁺ in SR is not as abundant as the SR of adult heart; so, the myocardium of the neonates, infants, and children is highly dependent on extracellular levels of Ca²⁺ for functioning normally, especially when considering the fact that the calcium transport system in the myocardium of infants and children is immature. These unique features of Ca²⁺ homeostasis in pediatric heart is among the main causes for reduced myocardial in this age group compared to the normal healthy adult (Bers 2002; Maier et al. 2005; Gustafsson and Gottlieb 2009; Asp et al. 2013).

The excitation-contraction coupling (ECC) involves a number of ongoing and interrelated events to act as a machine to promote cardiac function. The following steps occurring in sequential cascade constitute the ECC:

So, these three main proteins interact together in handling of Ca²⁺ homeostasis:

Functioning organelles of ECC are cell membrane, thick and thin filaments, T tubules, and sarcoplasmic reticulum:

There are a number of modulators which balance the different interactions in ECC (Yang et al. 2011; Asghari et al. 2014; Brunet et al. 2015; Motloch et al. 2016):

Myosin has a structured framework. First of all, the 15 nanometer myosin rods are composed of the following elements:

Then, one MHC plus two MLCs compose a single myosin strand (MS); so, we will have:
Afterward, two MSs woven together produce one myosin molecule (MM); in other words, each MM is composed of two MSs:
However, each MM resembles a “golf club” which has two functional domains: the four MLCs in the head region and the tail region of MM which is like the handle of the golf club (Fig. 3.1). Ca²⁺ trigger causes the head of MM to cross bridge with actin leading contractions. Also, TnI inhibits the crossbridges at the end of each interaction to detach actin from myosin head.

About 300 MMs collectively form together in a parallel fashion forming myosin rod (MR) which resembles “a bundle of golf clubs” collected together while their heads protrude out of the bundle and their bodies and handles are attached together (Fig. 3.6).

Titin is the most frequent filament after actin and myosin; “the largest protein known to date,” titin is a very giant filament extending from each side of the Z line toward the M line; it has been simply named as the “bidirectional molecular spring” of the cardiac sarcomere; in other words, during diastole, the extensible properties of titin help myocardial tissue to preserve its primary configuration, returning to the primary size of the heart; in this way, titin acts as a “passive force generator” in diastole; on the other hand, titin plays its role in restoration of sarcomere length when it is shorter than its slack length. Besides, titin has attachments with actin-myosin crossbridge sites through myosin-binding protein C (MBPC). This is why titin has a very strategic role in cardiac sarcomere to keep it stable during contraction and relaxation (Pyle and Solaro 2004; Solaro 2005; Kobirumaki-Shimozawa et al. 2014).

Titin has a specific structure which helps create its elastic role. Functionally speaking, titin has two segments:

On the other hand, if we want to explain titin based on a structural classification of the molecule, it has two parts:

The role of titin in “fine-tune passive myocardial stiffness” and “diastolic function and diastolic force generation” is highly dependent on phosphorylation of titin molecule by calcium-/calmodulin-dependent protein kinase II delta (CaMKIIδ); those regions of titin located in “I band” are important in phosphorylation mechanisms. Impairment in CaMKII-dependent phosphorylation of titin is considered as a major etiology for diastolic dysfunction. Mutations in those genes related to titin are often considered as the etiologic factor for dilated cardiomyopathy, since titin disruption ends to impairment of structure of the heart and its elasticity (LeWinter et al. 2007; Nishikawa et al. 2012; Hamdani et al. 2013a, b; Hidalgo et al. 2013; Kotter et al. 2013; Rain et al. 2014; McNally et al. 2015; Zile et al. 2015).

Titin stiffness could lead to RV diastolic dysfunction in pulmonary hypertension patients, of course in association with factors like reduced phosphorylation of cTnI and altered phosphorylation of Ca2+ (Rain et al. 2014).

Also, in heart failure patients, impaired phosphorylation of the thick filament protein myosin-binding protein C (cMyBP-C) has a main role especially in patients with diagnosis of familial hypertrophic cardiomyopathy due to mutations in MYBPC3 (Kuster et al. 2012).

TM is under the control of two parts of troponin complex: troponin T (TnT) and troponin I (TnI); in cardiac muscle, Ca²⁺ attachment to troponin C (TnC) causes TM to be detached from the actin-myosin crossbridge site; this is exactly the point which is inhibited by TM; in other words, Ca²⁺ inhibits TM; then, this “inhibition” exposes the “crossbridge site” to myosin molecule; this is exactly the myosin binding site on actin molecule known as crossbridge site or active site; in this process, when TM is pushed far from crossbridge sites, myosin crossbridge finds the opportunity to directly attach to this critical point, i.e., the crossbridge; and these interactions lead to sarcomere contraction. At the end of the contraction, when Ca²⁺ concentration in sarcomere falls, troponin I (TnI) augments the role of TM, in such a way that again TM becomes closer to crossbridge sites, attaches to crossbridge, and pushes myosin away from crossbridge; the final outcome is inhibition of contraction. In this process, the two most important modulators for sensitivity of sarcomere filaments to Ca²⁺ are the sarcomere length (i.e., Frank-Starling relationship) and the role of protein phosphorylation in sarcomere which causes posttranslational modification of these proteins; the reader can find detailed discussion in a number of reviews published in the last years (Hitchcock-DeGregori 2008; Kobayashi et al. 2008; Jagatheesan et al. 2010; Bai et al. 2013).

There are two specific inherited diseases involving impaired function of TM in Ca²⁺ attachment: dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); both are due to “missense mutations” in genes coding TM. In summary, in DCM, the mutation causes decreased sensitivity of TM to Ca²⁺ binding, while in HCM, the mutation ends to increased sensitivity of TM to Ca²⁺ (Bai et al. 2013; Redwood and Robinson 2013; Kalyva et al. 2014) (Fig. 3.7).

There are two Ca²⁺ binding sites (CBS) on C terminus (CBS III and CBS IV); Ca²⁺ is attached firmly to both of them; so none of them is involved in controlling Ca²⁺-dependent muscular contractions; however, these two Ca²⁺ binding sites (i.e., CBS III and IV) are attached to TnC and TnI. On the other hand, there are two other Ca²⁺ binding sites on the N terminus of TnC: CBS I and CBS II; however, CBS I cannot attach to Ca²⁺ firmly, while CBS II is the only and most important CBS that attaches to Ca²⁺ and performs the regulatory and modification roles of TnC in muscle contraction. Attachment of Ca²⁺ to CBS II on N terminus of TnC causes structural and functional changes in both “actin-TM” complex and troponin complex; these changes cause activation of the thin filament. TnC mutations are involved in both HCM and DCM (Marston and Redwood 2003; Kobayashi et al. 2008; Kekenes-Huskey et al. 2012; Craig et al. 2014; Kalyva et al. 2014; Kobirumaki-Shimozawa et al. 2014; Shi et al. 2015).

A main functional part of interactions between these proteins is the crossbridging phenomenon, a basic phenomenon with its integral role in myocardial contraction, which is based on continuous interactions between the thick and thin filaments.

Z disc, I band, A band, and M line (the following components are demonstrated in Fig. 3.8a, b): Sarcomeres are cylindrical repeating units; the margin of each sarcomere is Z disc or Z line.

Z in Z discs stands for Zuckung, a German name meaning twitch; Z discs are three-dimensional structures about 100 nm (0.1 μ) composing the margins of each sarcomere; in fact, Z discs are the border of two neighboring sarcomeres, and they divide the sarcomeres from each other. However, each Z disc is a complex of many proteins including those located at Z disc and those attached to Z disc.

Functionally, Z discs have the main following roles:

There is a pivotal band for the thick filaments called M band; these bands are in the Middle of the sarcomere, so M band. Both Z discs and M bands are transversally oriented multi-protein scaffolds (Stehle et al. 2009). On either side of each M band, thick filaments compose the “A band.” In fact, A band is the band on each side of the M band which is the region of thick filaments; the lateral border of A band contains the terminal segment of the thin filaments which, together with thick filaments, slide into each other during contraction and come out during relaxation (Tskhovrebova and Trinick 2010).

On the other side, the specific segment of the A band located in the center of A band which is devoid of thin filaments is called “H band” (Solaro 2005; Kobayashi et al. 2008).

In summary, the attachment of filaments of sarcomeres is as follows (Stehle et al. 2009):

The autonomic nervous system (ANS) as a portion of the peripheral nervous system continuously controls cardiovascular functions.

The ANS, on the other hand, is regulated by other centers such as the brain stem and hypothalamus.

The sympathetic and parasympathetic systems are the main component of ANS.

The preganglionic nerves of sympathetic system originate from T1-L2 segment of the spinal cord and enter the sympathetic chain ganglia located along the side of the viscera column (i.e., paravertebral ganglia). Postganglionic fibers of the cardiac sympathetic originate from the stellate ganglia and extend to different parts of the heart (SA and AV nodes, atria, and ventricles).

The long preganglionic nerves of cardiac parasympathetic system originate in the dorsal motor nucleus of the tenth cranial nerves (left and right vagi) or in the nucleus ambiguous. The short postganglionic nerves lie on epicardial surface and within the atrial and ventricular walls. There is no equal vagi distribution to different cardiac structures, because the vagi mainly affect SA and AV nodes and there is a slight distribution for atria and ventricles.

In the newborn heart, the number of α-adrenergic receptors is reduced; this is among the factors that limit the function of the left ventricle; also, the level of the circulating catecholamines increases dramatically to compensate for the limited function of the heart, an important fact that should be considered when anesthetizing a child or newborn especially for cardiac procedures; it is logic to avoid suppressing the sympathetic tone of the body in order to prevent decreased cardiac output.

Since the right and left sides of the embryonic structures are the sites for developing the SA and AV nodes, respectively, the SA node receives its ANS branches mainly from the right vagus and right stellate ganglion, and the AV node takes its branches mostly from the left vagus and left stellate ganglion. Sympathetic β-receptors are epicardial and parasympathetic muscarinic receptors are endocardial (Gordan et al. 2015).