Heart: Gross Structure and Myocardial Cells

6.2.1 Gross Structure and Size

The mammalian heart consists of the two receiving chambers—the atria—and two pumping chambers— ventricles. The size of heart is approximately 0.3-1.0% of the body weight and varies across species.

Birds possess larger hearts, higher stroke volumes, lower heart rates, and increased cardiac output than mammals of corresponding body mass, which contributes to the high aerobic energy input needed to sustain the flapping flight. The larger birds like geese, ducks, and swans tend to have proportionally smaller hearts in relation to their body mass than the smaller birds. Thus, heart mass in small birds such as the racing pigeons is about 1.1% of body mass, compared with 0.8% for the Pekin ducks. In the migratory birds, the heart becomes hypertrophic before migration, which could be due to their genetic potential to increase cardiac output and heart size either through seasonal humoral mechanisms or through natural selection over long term.

6.2.1.1 HeartChambers

6.2.1.1.1 Atria

The thin-walled, low-pressure atria receive the venous blood, function as elastic reservoir, and act as a primer pump, thereby enhancing ventricular filling. The right atrium has an average thickness of about 2-3 mm and receives blood from three veins: the superior vena cava, inferior vena cava, and coronary sinus.

6.2.1.1.2 Ventricles

Most of the heart’s weight is contributed by the ventricular myocardial mass. The right ventricle has an average thick­ness of about 4-5 mm. Trabeculae carneae, or elevated bundles of cardiac muscle fibers, produce a series of ridges in the inside of right ventricles. The cusps of tricuspid valve are connected to the chordae tendineae, which in turn are connected to cone-shaped trabeculae carneae called papillary muscles. Internally, the right ventricle is separated from the left ventricle by a partition called the interventricular septum. Blood passes from the right ventricle through the pulmonary valve (semilunar valve) into a large artery called the pulmo­nary trunk, which divides into right and left pulmonary arteries. The left ventricle, the thickest chamber of the heart (average thickness of 10-15 mm), forms the apex of the heart. Like the right ventricle, the left ventricle has trabeculae carneae and chordae tendineae that anchor the cusps of the mitral valve to papillary muscles. Blood passes from the left ventricle through the aortic valve (semilunar valve) into the aorta.

The Burmese python (Python molurus) shows a rapid extraordinary 40% increase in ventricular mass within 48-72 h after their biannual feeding, which could be attributed to a specific set of fatty acids that appear to pro­mote myocardial hypertrophy, not hyperplasia, and an increased expression and activity of superoxide mutase—a cardioprotective free radical scavenger.

6.2.1.1.3 Myocardial Thickness and Functional Correlation

The thickness of the myocardial chambers varies according to their function. While the thick-walled ventricles pump blood under higher pressure over longer distances, the thin-walled atria pump blood under lower pressure into the adjacent ventricles. Despite the fact that the right and left ventricles function as two independent pumps that discharge the same amount of blood at once, the right side has a far lesser resistance and pumps blood only a short distance to the lungs at lower pressure and has lesser resistance to blood flow. The left ventricle pumps blood through great distances to all other parts of the body at higher pressure, and the resistance to blood flow is larger. Therefore, the left ventricle works much harder than the right ventricle to maintain the same rate of blood flow, and hence, the muscular wall of the left ventricle is considerably thicker than the right ventricular wall.

During systole, the right ventricular free wall moves toward the interventricular septum due to the contraction of the spiral muscles. Systole in the left ventricle also functions to assist ejection from the right ventricle by the curvature of the septum, pulling the right ventricular free wall toward the septum (called left ventricular aid).

6.2.1.2 CardiacValves

The four fibrous cardiac valves, namely, the atrioventricular (AV) valves that separate the atria from the ventricles and the semilunar valves positioned between the ventricles and the great arteries (pulmonary artery and aorta), aid to regulate the blood flow into cardiac chambers during the various phases of the cardiac cycle. The passive opening and closing of these valves occur in response to pressure changes produced by contraction and relaxation of the four muscular chambers, and the orientation of the valves helps to maintain a unidirec­tional flow of blood.

6.2.1.2.1 Atrioventricular (AV) Valves

The atrioventricular valves (tricuspid and bicuspid valves) located between the atrium and the ventricles, in open posi­tion, have the rounded ends of the cusps project into the ventricles.

6.2.1.2.2 SemilunarValves

The aortic and pulmonary valves are known as the semilunar (SL) valves because they have three crescent moon-shaped cusps, which are attached to the arterial wall by their convex outer margin. The semilunar valves allow blood to leave the heart and enter arteries, but they stop blood from returning to the ventricles. The free borders of the cusps project into the lumen of the artery. The semilunar valves open when the ventricular pressure exceeds the pressure in the arteries, allowing ejection of blood from the ventricles into the pul­monary trunk and aorta. As the ventricles relax, blood starts to flow back toward the heart for a short period of time until the semilunar valve closes.

6.2.2 Physiology of Cardiac Muscles

Cardiac muscles contract millions of times over the lifetime of a domestic animal, which exhibits their unique endurance potential. Cardiac muscle is involuntary and striated and has sarcomeres with actin and myosin filaments and other organelles, which have their own functional and anatomical differences.

There are two specialized types of cardiac muscle cells:

1. Contractile cells, comprising 99% of the cardiac muscle cells, perform the mechanical work of pumping. These cells normally do not initiate the action potentials and are specialized for contraction and impulse conduction.

2. Autorhythmic cells are small but extremely vital for car­diac functioning. Instead of contracting, they are specialized to initiate and propagate the action potentials that cause the working cells to contract. Although the pacemaker, conduction, and working cells account for the majority (>70%) of the heart’s mass, they only consti­tute one-third of the total number of cells in the heart. The remaining cells are fibroblasts, endocardial cells, endothe­lial cells, and vascular smooth muscle cells (details are discussed in Sect. 10.3.2).

6.2.2.1 Myocardial Cells

In comparison to the skeletal muscle fibers, the cardiac mus­cle fibers are shorter in length, branched, and less circular in transverse section. A mature cardiac muscle fiber is 85-100 μm long and has a diameter of about 15 μm. Each myocardial cell has a centrally located nucleus and is packed with contractile myofibrils consisting of sarcomeres joined end to end at their Z lines. Intercalated discs are specialized paired interdigitating membrane junctions that connect the two ends of adjacent cells in series. These intercalated discs have three types of functional specializations: fascia adherens, desmosomes, and gap junctions. Fascia adherens present on the transverse segment of the disc serves as a locus for insertion of actin myosin filaments and forms a strong connection between adjacent fibers. Desmosomes are round bodies found on the transverse segment of the disc and that mechanically hold cells together. They allow the transmis­sion of the force of contraction and produce the mechanical syncytium. They are particularly abundant in heart, which is constantly subjected to considerable mechanical stress.

Gap junctions are found on the longitudinal segments of the discs and contain channels that allow free diffusion of ions between the cells with low electrical resistance. Gap junctions allow the entire myocardium to contract as a single, coordinated electrical syncytium. Gap junctions are elon­gated and numerous in Purkinje cells where conduction is rapid, whereas the gap junctions are small and sparse in SA node and AV nodal cells.

6.2.2.1.1 Sarcoplasmic Reticulum and Tubular System

The sarcoplasmic reticulum consists of a network of anatomizing thin-walled tubules that invests into the sarco­mere and has the main function of providing the majority of Ca²⁺ ions required to trigger the myofilaments and to resequester Ca²⁺ from the myoplasm allowing for relaxation. The sarcoplasmic reticulum has two main regions: junctional sarcoplasmic reticulum (jSR), which confronts the surface membrane’s invaginations called transverse tubules (T-tubules) directly, and extrajunctional free sarcoplasmic reticulum (fSR), which is situated near the myofibrils. jSR forms extended, flattened cisternae, which have sets of closely grouped structures (“feet”) that represent the cardiac SR Ca²⁺ release channels, also known as ryanodine receptors (RyR2s), and contain the Ca²⁺-binding protein, calsequestrin-2 (CASQ2). On the other hand, the fSR is devoid of CASQ2, and its external surface has Ca²+ adeno­sine triphosphatase (ATPase). Calsequestrin, the major Ca²⁺- binding protein in sarcoplasmic reticulum, acts as the major Ca²⁺ storage and buffering protein and is an important regu­lator of Ca²⁺ release channels in both skeletal and cardiac muscle.

Phospholamban, a sarcoplasmic reticulum protein, is a key regulator of cardiac contractility. In its dephosphorylated state, it regulates SR Ca²+ sequestration by inhibiting the SR Ca²⁺-ATPase (SERCA) (which transports calcium from cyto­sol into the sarcoplasmic reticulum). Upon phosphorylation, the inhibitory effect of phospholamban on the SERCA is removed leading to faster Ca²⁺ uptake into the sarcoplasmic reticulum.

Myocardial cells of the avian species lack transverse tubules, which are prominent in mammalian cardiac muscles. Similarly, the avian myocytes lack the M-band of the cyto­skeleton structure that cross-links the myosin and titin filaments in the middle of the sarcomere.

6.2.2.1.2 Myocardial Cell Organelles

Mitochondria are more numerous in cardiac muscle and larger, and they make up about 40% of the cytoplasmic volume compared with only about 2% in skeletal muscle. In some myocardial cells, the mass of the mitochondria equals that of the myofibrils. Cardiac muscle cells stop contracting after about 30 s of oxygen deprivation, thus reflecting the reliance of cardiac muscle on aerobic metabolism. Glycogen granules are found in large numbers and are evenly dispersed in cardiac muscle. Lipid droplets, which are the predominant energy source when engaged in aerobic metabolism, are frequently found located adjacent to mitochondria.

6.2.2.1.3 Functional Syncytium

The cardiac muscle fibers do not fuse with each other and do not form a morphological syncytium, but because of their branching and bifurcations, they form a functional syncytium that allows coordinated contraction. The electrical impulse spreads from one cardiac cell to all the other cells that are joined by gap junctions in the surrounding muscle mass so that they become excited and contract as a single, functional syncytium. The atria and the ventricles each form a separate functional syncytium and contract as separate units. This division allows the atria to contract a short time ahead of ventricular contraction, which is vital for effective heart pumping. The synchronous contraction of the myocytes in the atrial and ventricular walls produces the force needed to eject the received blood. Action potentials are not conducted from the atrial syncytium into the ventricular syncytium due to the lack of gap junctions joining the atrial and ventricular contractile cells and also due to the presence of an electrically nonconductive fibrous tissue that surrounds the valves and separates the atria and the ventricles. Instead, the action potentials are conducted only by way of a specialized con­ductive system, the atrioventricular (AV) bundle that facilitates and coordinates transmission of electrical impulse from the atria to the ventricles, thus ensuring synchronization between atrial and ventricular pumping.

6.2.2.2 Metabolism and Energetics of Working Myocardial Cells

Under normal conditions, the metabolic system of cardiac cells relies nearly entirely on aerobic metabolism, which continuously supplies high-energy phosphate bonds for mechanical and chemical work. The cardiac myocytes have an abundance of energy-generating mitochondria, and they receive a rich blood supply, which is delivered by about one capillary for each myocardial to support their rhythmic, con­tractile activity. Cardiac muscle also has an abundance of myoglobin, which stores O₂ within the heart for immediate use.

The basal oxygen consumption by the myocardium is about 2 mL/100 g/min, and by the beating heart, it is about 9 mL/100 g/min at rest which increases further during exercise.

The heart can use a variety of substrates (glucose and fatty acids) to oxidatively regenerate ATP depending upon avail­ability. Usually, the cardiac muscle cells use free fatty acids as their major fuel for metabolism. Glucose and lactate are important contributors. For each mole of O₂ consumed, there is a 53.7% higher energy production from the metabolism of glucose than from the metabolism of palmitate. The caloric value of the stored high-energy phosphate bonds produced by the oxidation of a gram of palmitate is 2.4 times greater than that produced by the oxidation of a gram of glucose, but at a greater relative expenditure of oxygen than that produced by the oxidation of glucose. Hence, when oxygen is abundant and food is scarce, utilizing fatty acids for fuel is advanta­geous as opposed to using glucose. Following a high- carbohydrate meal, the heart can adapt itself to utilize carbohydrates (primarily glucose) almost exclusively. The reverse occurs when food is plentiful and oxygen is scarce. The heart utilizes fatty acids (60-70%) and carbohydrates (~30%) under postabsorptive state. During exercise, lactate can be used in place of glucose. Under diabetic acidosis, amino acids and ketones are utilized as metabolic fuel. The coronary circulation is unable to provide the heart with the metabolic substrates it needs to support aerobic metabolism during ischemia and hypoxia; thus, the heart uses glycogen as a source of energy for the anaerobic synthesis of adenosine triphosphate (ATP) and the creation of lactic acid. As the cardiac muscle is highly adaptable and can shift metabolic pathways to use whichever nutrient is available, the primary danger of insufficient coronary blood flow is oxygen defi­ciency and not fuel shortage.

6.2.2.3 Properties of Myocardial Cells

Conductivity: Cardiac muscle cells are capable of transmit­ting action potentials. In spite of being separated by plasma membranes, the individual cells pass the impulse from one cell to another cell through the specialized gap junctions in the intercalated discs.

Contractility: Contractility refers to the ability of the myocardial tissue to shorten in length (contraction) after receiving a stimulus. The contractile properties of the cardiac muscle are influenced by many factors.

Following are the contractile properties of myocardial cells:

All or none principle: If at all the cardiac muscle responds to a stimulation, it contracts with maximum strength (i.e., all contractions of the cardiac muscle are maximum) under the prevailing physical and chemical environment, i.e., the heart muscle contracts maximally when stimulated with either minimum or maximum strength of stimulus. The all or none law is due to the syncytial nature of the cardiac muscle.

Staircase phenomenon: The cardiac muscle responds with increasing degree of strength for the first 3-5 stimuli when an effective stimulus is applied repeatedly with a short interval (1-2 s), after which the reaction is constant. This is referred to as staircase phenomenon or Treppe. When the interval between two stimuli of same strength is very short, the physical and chemical changes known as bene­ficial effects, occurring during the first response, persist and these changes facilitate the second one giving greater response. This progressive rise in tension after an increase in the heart rate was first observed by Henry Bowditch in 1871. The staircase phenomenon is caused due to an increase in sarcoplasmic reticulum Ca²⁺ content and release, which in turn occurs by three mechanisms. First, during each action potential plateau, Ca²⁺ enters the cell through L-type Ca²⁺ channels, and the more number of action potentials per minute provides a longer aggregate period of Ca²⁺ entry through these channels. Secondly, depolarization during the plateau of an action potential causes the Na-Ca exchanger (NCX1) to operate in the reverse mode, permitting Ca²⁺ to enter into the cell. At higher heart rates, these depolarizations occur at increased frequency and are accompanied by an increase in intracel­lular Na+, which accentuates the reversal of NCX1, both of which enhance Ca²⁺ uptake. Third, the rising intracel­lular Ca²⁺, through calmodulin (CaM), activates CaM kinase II, which leads to phosphorylation of phospholamban (PLN); phosphorylation of PLN in turn stimulates sarcoendoplasmic calcium ATPase (SERCA₂a), thereby sequestering the Ca²⁺ in sarcoplas­mic reticulum that had entered the cell as a result of the first two mechanisms.

Refractory period: When an excitable tissue is responding to a stimulus, it may not produce another response for a subsequent stimulation for a shorter period. This period of unresponsiveness of cardiac muscle is called as refractory period. The refractory period of a cardiac muscle fiber lasts longer than the contraction itself. As a result, another contraction cannot occur until relaxation is well under­way. The refractory period is longer in cardiac muscle than skeletal muscles, and hence cardiac muscle cannot be thrown into continuous contractions by a series of rapid stimuli, i.e., cardiac muscle cannot be tetanized.

After initial stimulation, there is an absolute refractory phase, which is a very brief period during which there is no reaction at all. This phase is followed by a short period of partial responsiveness, during which the cardiac muscle can be stimulated by stronger stimuli, and this period is referred to as relative refractory period. The period of systole of cardiac muscle is the absolute refractory period (atria 0.15 s, ventricle 0.25 s), and relative refractory period occurs dur­ing early diastole (atria 0.03 s, ventricle 0.05 s).

Regeneration: Regeneration of cardiac muscle fibers does not occur, and if myocardial fibers die, they are replaced by fibrous noncontractile scar tissue. During the embryo­genesis of skeletal muscle, once the cells have differentiated to the point where they are capable of con­traction, there is no further cell division or increase in DNA content. In the adult animal, increase in myocardial mass, particularly in an adult animal, can be accomplished only through the hypertrophy of already differentiated cardiac cells, leading to the enlargement and multiplica­tion of intracellular structures such as myofilaments and mitochondria.

Extrasystoles: Extrasystoles refer to the additional heartbeats, initiated by an irregular internal or external excitation source. Extrasystoles are induced by a hypersensibility of the autonomous nervous system or by mechanical, chemical, or pharmacological stimuli.

Electrical excitation in cardiac myocytes is linked to contrac­tion through increase in intracellular calcium that occurs with each action potential. Most of the increase in intra­cellular calcium results from Ca²⁺ release from the sarco­plasmic reticulum through release channels (ryanodine receptors) (RyRs), which in turn is triggered by Ca²⁺ entry through L-type channels in the cell membrane. This process of Ca²⁺-induced Ca²⁺ release (CICR) involves positive feedback and is potentially unstable. The cell controls this potential instability by grouping the RyRs into spatially segregated clusters. In a resting myocyte, spontaneous release of sarcoplasmic reticulum Ca²⁺ from a cluster of ryanodine receptors (RyRs) will appear as a spatially restricted (2 μm) Ca²+ spark that will not spread to neighboring regions. Under conditions wherein there is Ca²⁺ overload, RyRs become more sensi­tive to increases in intracellular calcium, wherein a spon­taneous Ca²⁺ spark can trigger release from neighboring clusters of RyRs, and a regenerative Ca²⁺ wave can result. This Ca²+ wave, propagating roughly at 100 μmis, raises the intracellular calcium from 100 nM to about 1 μM. This results in a delayed afterdepolarization and, if it is large, can cause an extrasystole or ectopic action potential.

Post-extrasystolic potentiation: Post-extrasystolic potentia­tion refers to the increase of myocardial contractility that follows a premature beat. When a premature beat occurs, most of the ryanodine receptors are refractory to activation, causing a diminished Ca²+ transient and thus a less forceful contraction. After the premature beat, sar­coplasmic reticulum Ca²⁺ load is increased in a number of ways. First, while less Ca²⁺ is released, Ca²⁺ loading of the sarcoplasmic reticulum continues. Next, low Ca²⁺ transient during the premature beat opposes less negative feedback to sarcolemmal Ca²+ influx, and this extra Ca²+ further increases sarcoplasmic reticulum Ca²⁺ content and all ryanodine receptor channels recover from inactivation. At the post-extrasystolic beat, all the Ca²+ sequestered during the previous beats is released, resulting in increased force of the post-extrasystolic beat.

6.3