The Cardiac Pump

Cardiac Muscle (Myocardial) Cell Morphology

Several important morphological and functional differences exist between myocardial cells ( Figs. 4.1–4.4 ) and skeletal muscle cells. However, the contractile elements within cardiac and skeletal muscle are quite similar. Each skeletal and cardiac muscle cell is made up of sarcomeres (from Z line to Z line) that contain thick filaments composed of myosin (in the A band) and thin filaments containing actin. The thin filaments extend from the point where they are anchored to the Z line (through the I band) to interdigitate with the thick filaments. Shortening occurs by the sliding filament mechanism, as in the case of skeletal muscle. Actin filaments slide along adjacent myosin filaments by cycling of the intervening crossbridges, thereby bringing the Z lines closer together and shortening the cell.

A striking difference between cardiac and skeletal muscle is that myocardial cells are all electrically and mechanically connected within the wall of a particular heart chamber. At the junction of the longitudinal ends of each pair of cardiac cells, the surface membranes are folded and intercalated with the membrane of its neighbor. These regions are known as intercalated disks (IDs) and contain the specialized proteins and structures that provide the mechanical and electrical connections between the two cells. Desmosomes are comprised of certain cell adhesion proteins (cadherins) and provide a strong, force transmitting connection between the ends of the myocardial cells. As the wave of excitation approaches the end of a cardiac cell (see Fig. 2.17 ), the spread of excitation to the next cell depends on the electrical conductance of the boundary between the two cells. As discussed previously (see Chapter 2 ), gap junctions (GJs or nexuses) with high conductance are present in the IDs between adjacent cells (see Fig. 4.2C–D ). GJs are sparse between the lateral borders of the cells and thus cardiac impulses progress more rapidly in a direction parallel to (isotropic) the long axes of the constituent fibers than in a direction perpendicular to (anisotropic) the long axes of those fibers. Thus IDs that connect the cardiac cells contain the structures, desmosomes, and GJs that allow the rapid and efficient activation and contraction of the ventricular and atrial muscle tissue.

Cardiac and fast skeletal muscle fibers differ in the number of mitochondria in the two tissues. Fast skeletal muscle, which is called on for relatively short periods of repetitive or sustained contractions and which can metabolize anaerobically and build up a substantial O ₂ debt, has relatively few mitochondria in its fibers. In contrast, cardiac muscle, which contracts repetitively for a lifetime and requires a continuous supply of O ₂ , is very rich in mitochondria (see Figs. 4.1–4.3 ). Rapid oxidation of substrates with the synthesis of adenosine triphosphate (ATP) can keep pace with the myocardial energy requirements because of the large numbers of mitochondria containing the respiratory enzymes necessary for oxidative phosphorylation (see later in this chapter).

To provide adequate O ₂ and substrate for its metabolism, the myocardium is endowed with a rich capillary supply, about one capillary per fiber. Thus diffusion distances are short, and O ₂ , CO ₂ , substrates, and waste material can move rapidly between the myocardial cell and capillary.

Ventricular muscle cells and skeletal muscle cells have a well-developed system of invaginations of the surface membrane, known as transverse tubules, or T-tubules. In ventricular cells, the T-tubules run into the cells at the Z-discs (or Z line). In mammalian skeletal muscle however, T-tubules penetrate at the level of the A–I band junction. The atrial cells of small mammals do not contain T-tubules. The atrial cells of large mammals, such as sheep, horses, and humans, are now known to contain a T-tubule system, although it is less extensive than that found in ventricular cells. In all muscle cells, the primary function of T-tubules is to conduct the electrical excitation into the interior of the muscle cell, such that excitation-contraction coupling occurs near all the myofibrillar bundles (see later in this chapter). The T-tubule lumina are continuous with the bulk interstitial fluid. In mammalian ventricular cells, adjacent T-tubules are interconnected by longitudinally running or axial tubules that form an extensively interconnected lattice of intracellular tubules (see Fig. 4.3 ). This T-tubule system is open to the interstitial fluid, is lined with a basement membrane continuous with the surface sarcolemma, and contains micropinocytotic vesicles. Thus in myocardial cells, the myofibrils and mitochondria have ready access to a space continuous with the interstitial fluid.

A network of sarcoplasmic reticulum (SR) (see Fig. 4.3C ) consisting of small-diameter sarcotubules also surrounds the myofibrils; these sarcotubules are believed to be closed because colloidal tracer particles (2 to 10 nm in diameter) do not enter them. They do not contain abasement membrane. Flattened elements of the SR are often found close to the T-tubule system and to the surface sarcolemma, forming “dyads” (see Fig. 4.4 ).

Structure of the Heart: Atria, Ventricles, and Valves

The mammalian heart has four chambers, consisting of two pumps in series. The right heart, consisting of the right atrium and right ventricle, pumps venous blood to the pulmonary circulation; and the left heart, consisting of the left atrium and left ventricle, pumps oxygenated blood into the systemic circulation at relatively high pressure ( Figs. 4.5 and 4.6 ). The atria are thin-walled, low-pressure chambers that function more as large reservoirs of blood for their respective ventricles than as important pumps for the forward propulsion of blood. The ventricles are a continuum of muscle fibers that originate from the fibrous skeleton at the base of the heart (chiefly around the aortic orifice). These fibers sweep toward the apex at the epicardial surface and also pass toward the endocardium as they gradually undergo a 180-degree change in direction ( Fig. 4.7 ). Thus they lie parallel to the epicardial fibers and form the endocardium and papillary muscles (see Fig. 4.5 ). At the apex of the heart, the fibers twist and turn inward to form papillary muscles. At the base and around the valve orifices (see Fig. 4.6 ), the fibers form a thick, powerful muscle that not only decreases ventricular circumference for ejection of blood but also narrows the atrioventricular (AV) valve orifices to help close the valve.

Ventricular ejection occurs when the circumference is reduced and the longitudinal axis decreases with descent of the base of the heart. The earlier contraction of the apical part of the ventricles, coupled with approximation of the ventricular walls, propels the blood toward the outflow tracts. The right ventricle, which develops a mean pressure about one seventh of that developed by the left ventricle, is considerably thinner than the left. The cardiac valves consist of thin flaps of flexible, tough, endothelium-covered fibrous tissue firmly attached at the bases to the fibrous valve rings. Movements of the valve leaflets are essentially passive, and the orientation of the cardiac valve is responsible for unidirectional flow of blood through the heart. There are two types of valves in the heart—the AV valves and the semilunar valves (see Figs. 4.5 and 4.6 ).

Excitation-Contraction Coupling Is Mediated by Calcium

In cardiac muscle, as in skeletal muscle, a rise in cytoplasmic Ca ⁺⁺ initiates contraction, and the strength of the contraction depends on both the magnitude of the rise in cytoplasmic [Ca ⁺⁺ ] and the initial length of the sarcomeres (see Fig. 4.12 ). Certain cellular processes ( Fig. 4.8 ) participate in controlling the cytoplasmic Ca ⁺⁺ concentration during the heartbeat, and thus they are major determinants of the ability of the heart to contract. The processes that control Ca ⁺⁺ are generally thought to control the ability of the heart to contract at a given cardiac cell length; this is known as cardiac contractility . The influence of cardiac cell length on the strength of contraction is referred to as cardiac mechanics .

Initially, a wave of electrical excitation (action potential) spreads rapidly along the myocardial sarcolemma from cell to cell via gap junctions. Excitation also spreads to the cell interior via the T-tubules, which invaginate the cardiac fibers at the Z lines. An early and important experimental observation was that local electrical stimulation at the Z line elicits a localized contraction of adjacent myofibrils. During the plateau (phase 2) of the action potential, Ca ⁺⁺ permeability of the sarcolemma increases. Ca ⁺⁺ enters the cell through voltage-dependent L-type Ca ⁺⁺ channels in the sarcolemma and in the T-tubules (see Fig. 4.8 ). The Ca ⁺⁺ channel protein is called the dihydropyridine (DHP) receptor because it has high affinity for this group of Ca ⁺⁺ channel antagonists. Phenylalkylamines, such as verapamil, also block L-type Ca ⁺⁺ channels. Physiologically, opening of Ca ⁺⁺ channels is facilitated by phosphorylation of the channel proteins by a cyclic adenosine monophosphate (cAMP)-dependent protein kinase. The primary source of extracellular Ca ⁺⁺ is the interstitial fluid (1 mM Ca ⁺⁺ ). Some Ca ⁺⁺ also may be bound to the sarcolemma and to the glycocalyx , a mucopolysaccharide that covers the sarcolemma. The amount of Ca ⁺⁺ that enters the cell from the extracellular space through the L-type surface membrane Ca ⁺⁺ channels (I _Ca,L ) is not sufficient to induce physiologically significant contraction of the myofibrils. However, this Ca ⁺⁺ induces the release of a much larger amount of Ca ⁺⁺ from the intracellular Ca ⁺⁺ stores in the SR, sufficient to activate contraction. The Ca ⁺⁺ leaves the SR and enters the cytoplasm through SR calcium release channels, also called ryanodine receptors (RyRs), foot proteins or junctional processes (JP) (see Fig. 4.4 ). This process is known as Ca ⁺⁺ -induced release of Ca ⁺⁺ , or CICR, in which the binding of Ca ⁺⁺ to RyRs opens the channel pore, releasing Ca ⁺⁺ from the SR into the junctional space and cytoplasm. Opening of RyRs requires a relatively high [Ca ⁺⁺ ] in the junctional space around them, compared with levels of [Ca ⁺⁺ ] achieved in the cytoplasm. A key observed characteristic of CICR is that, with respect to the whole cell, the amount of Ca ⁺⁺ released from the SR is controlled by the Ca ⁺⁺ that enters via the L-type Ca ⁺⁺ channels. Thus the Ca ⁺⁺ current (I _Ca,L ) during the action potential (see Fig. 2.12 ) is a key regulator of the strength of the contraction. As a result of CICR, the cytosolic free Ca ⁺⁺ increases from a resting level of about 0.1 μM to 1 to 10 μM, and the Ca ⁺⁺ binds to the protein troponin C. The Ca ⁺⁺ -troponin complex interacts with tropomyosin to unblock active sites between the actin and myosin filaments, allowing crossbridge cycling and hence contraction of the myofibrils (systole). Several mechanims have been suggested, most likely within the lumen of the SR, to terminate SR Ca ⁺⁺ release. Depletion of the amount of Ca ⁺⁺ within the SR store is also involved in terminating SR Ca ⁺⁺ release.

CICR is a process that could result in uncontrolled release of Ca ⁺⁺ from the SR because the small amount of Ca ⁺⁺ that enters the cell via the Ca ⁺⁺ channels induces the release of a much larger amount of Ca ⁺⁺ from the SR via the RyRs. Possibly, Ca ⁺⁺ released from the SR would itself trigger further SR Ca ⁺⁺ release. Nevertheless, control of the amount of Ca ⁺⁺ released from the SR is a fundamental characteristic of heart cells, and this control regulates the strength of the heartbeat. SR Ca ⁺⁺ release is controlled by L-type Ca ⁺⁺ channels. The explanation for this apparently paradoxical control of SR Ca ⁺⁺ release by the Ca ⁺⁺ current (I _Ca,L ) lies in the “local control” theory of cardiac excitation-contraction coupling ( Fig. 4.9 ). The key elements of this theory for ventricular muscle cells are that (1) SR Ca ⁺⁺ release normally occurs only at junctions between T-tubules and the SR at the Z lines of sarcomeres, and (2) a relatively high [Ca ⁺⁺ ] is required to activate release from the RyRs. The physical separation of release sites from each other, and the requirement for a high [Ca ⁺⁺ ] for activation of release means that Ca ⁺⁺ released from one site does not normally reach the next site in sufficient concentration to activate further release. A locally high concentration of Ca ⁺⁺ is provided in the T-tubule–SR junction by the Ca ⁺⁺ entering that space through L-type Ca ⁺⁺ channels. Experimentally, the release of Ca ⁺⁺ at a single T-tubule–SR junction is visible in the form of a “Ca ⁺⁺ spark,” which is a highly localized increase in [Ca ⁺⁺ ]. Ca ⁺⁺ sparks during excitation of ventricular cardiac cells arise only at T-tubules, and these Ca ⁺⁺ sparks do not spread to the next T-tubule–SR junction. Voltage-clamp studies have shown that Ca ⁺⁺ sparks are triggered at T-tubule–R junctions by Ca ⁺⁺ entering via voltage-activated L-type Ca ⁺⁺ channels (see Fig. 4.9C and D ). Multiple Ca ⁺⁺ sparks summate to produce the whole-cell Ca ⁺⁺ transient (see Fig. 4.9E ). Furthermore, the number of Ca ⁺⁺ sparks occurring during depolarization is controlled by the number of L-type Ca ⁺⁺ channels that are activated, which is the magnitude of the Ca ⁺⁺ current, I _Ca,L . Therefore during the Ca ⁺⁺ current of the action potential, the whole-cell Ca ⁺⁺ transient is effectively controlled by I _Ca,L (and the mechanisms controlling the Ca ⁺⁺ available for release in the SR).

Mechanisms that raise systolic Ca ⁺⁺ increase the developed force, and those that lower Ca ⁺⁺ decrease the developed force. For example, catecholamines increase Ca ⁺⁺ entry into the cell by phosphorylation of the Ca ⁺⁺ channels via a cAMP-dependent protein kinase. Interestingly, when catecholamines enhance myocardial contractile force, they also elicit a limiting action by decreasing the sensitivity of the contractile machinery to Ca ⁺⁺ by phosphorylation of troponin I (see Fig. 4.8 ). When V _m is positive and when cytoplasmic [Ca ⁺⁺ ] is high, the Na ⁺ /Ca ⁺⁺ exchanger can bring Ca ⁺⁺ into the cell. An increase in systolic Ca ⁺⁺ is also achieved by increasing extracellular Ca ⁺⁺ or decreasing the Na ⁺ gradient across the sarcolemma.

The sodium gradient can be reduced by increasing intracellular Na ⁺ or decreasing extracellular Na ⁺ . Cardiac glycosides increase intracellular Na ⁺ by inhibiting the Na-K pump, which results in an accumulation of Na ⁺ in the cells. The elevated cytosolic Na ⁺ reverses the Na ⁺ /Ca ⁺⁺ exchanger so that less Ca ⁺⁺ is removed from the cell. This Ca ⁺⁺ is stored in the SR. A lowered extracellular Na ⁺ results in a reduction in Na ⁺ entry into the cell and hence less exchange of Na ⁺ for Ca ⁺⁺ (see Fig. 4.8 ). Developed tension is diminished by a reduction in extracellular Ca ⁺⁺ , by an increase in the Na ⁺ gradient across the sarcolemma, or by administration of Ca ⁺⁺ blockers that prevent Ca ⁺⁺ from entering the myocardial cell (see Fig. 2.15 ).

At the end of systole, the Ca ⁺⁺ influx ceases, and the SR is no longer stimulated via CICR to release Ca ⁺⁺ . The SR avidly takes up Ca ⁺⁺ with an ATP-energized Ca ⁺⁺ pump that is regulated by phospholamban . When phospholamban is phosphorylated by cAMP-dependent protein kinase (see Fig. 4.8 ), its inhibition of the Ca ⁺⁺ pump is relieved. Phosphorylation of troponin I inhibits the Ca ⁺⁺ binding of troponin C, permitting tropomyosin to again block the sites for interaction between the actin and myosin filaments, and relaxation (diastole) occurs (see Fig. 4.8 ).

Cardiac contraction and relaxation are both accelerated by catecholamines and adenylyl cyclase activation. The resulting increase in cAMP activates cAMP-dependent protein kinase, which phosphorylates the Ca ⁺⁺ channel in the sarcolemma. This allows a greater influx of Ca ⁺⁺ into the cell and thereby increases contraction. However, it also accelerates relaxation by phosphorylating phospholamban, which enhances Ca ⁺⁺ uptake by the SR and by phosphorylating troponin I, which inhibits the Ca ⁺⁺ binding of troponin C. Thus the phosphorylations by cAMP-dependent protein kinase serve to increase both the speed of contraction and the speed of relaxation.

The Ca ⁺⁺ that enters the cell to initiate contraction must be removed during diastole. The removal is primarily accomplished by the exchange of 3 Na ⁺ for 1 Ca ⁺⁺ (see Fig. 4.8 ). Ca ⁺⁺ is also removed from the cell by a pump that uses ATP to transport Ca ⁺⁺ across the sarcolemma (see Fig. 4.8 ).

Mechanics of Cardiac Muscle

The strength of contraction of individual myocardial cells is determined not only by the state of the excitation-contraction coupling processes but also by the initial length of the sarcomeres (see Fig. 4.1 ), which determines the extent that actin-myosin crossbridges can form and cycle (thus generating force and/or shortening). This length dependence of contraction can be observed in individual cardiac cells, in bundles of cells (as in ventricular strips or papillary muscles), and in the intact ventricles of the whole heart in the living organism. In the whole heart, the length dependence of cardiac contraction is manifested by the Frank-Starling law of the heart, which is a major determinant of cardiac output. In the heart, the blood’s pressure constitutes both a load on the heart that determines the length of the cardiac cells before each heartbeat (the preload), and a load on the heart experienced as it ejects blood into its outflow tracts after it is electrically activated to contract (the afterload). The preload and afterload experienced by the heart in the intact circulation are determined by systemic factors, such as total peripheral resistance and blood volume, as explained further in this chapter and in Chapter 10 .

Preload Determines the Strength of Cardiac Contraction

For an isolated strip of ventricular cardiac muscle or an isolated papillary muscle in an experimental situation ( Fig. 4.10 ), preload is the force (load) on the muscle before (pre-) it is activated to contract. The preload applies tension to the muscle and stretches it passively to a new length. In the heart, preload is the stress exerted on the ventricle during diastole and can be represented by the Laplace equation for a thick-walled sphere. Thus muscle can be characterized by a passive length-tension relationship, obtained by measuring length at different preloads. Preload also determines the strength of an active , isometric contraction that begins from a particular length. The muscle may be forced to contract isometrically by the addition of a very large afterload that the muscle will not be able to lift (see Fig. 4.10 ). (The further lengthening of the muscle that would be caused by the afterload is prevented with a physical stop.) Then, upon electrical stimulation, the muscle contracts isometrically (i.e., without shortening) and develops the maximum active force of which it is capable, from that initial length. Increasing preload always stretches the muscle further, causing both increased initial length ( Fig. 4.11A ) and, up to a point, greater active force development. The total tension within the muscle at the peak of the contraction is the sum of the passive tension and active tension (see Fig. 4.11B ). When contractility is increased, as by norepinephrine (see Fig. 4.8 ), the active tension and total tension are greatly increased (see Fig. 4.11C ). The passive tension is largely unaffected when contractility increases, and thus the increase in total tension is caused entirely by greater active tension. Conversely, a reduction in contractility, as might be caused by pharmacological block of L-type Ca ⁺⁺ channels, results in reduced total tension, largely accounted for by decreased active tension development. The fact that active tension generated by cardiac muscle rises steeply with increasing initial muscle length is critical to the performance of the heart, allowing it to contract more strongly if it is stretched by a greater volume of blood before contraction.

The detailed relationship between sarcomere length and tension (passive and active) has also been examined ( Fig. 4.12 ). Cardiac sarcomere length has been determined with electron microscopy in papillary muscles and intact ventricles rapidly fixed during systole (contracted) or diastole (relaxed). The developed force is maximal when cardiac muscle begins its contractions at initial sarcomere length of 2.2 μm. At this length, there is optimal overlap of thick and thin filaments, and a maximal number of possible cross-bridge attachments. Although skeletal and cardiac muscles show somewhat similar length-tension relationships (see Fig. 4.12 ), the normal operating ranges of their sarcomere lengths are distinctly different. Cardiac muscle does not normally operate at very short (<1.8 μm) or very long (>2.2 μm) sarcomere lengths. Furthermore, the ascending limb of the cardiac muscle length-tension relation is very steep over the range of 1.8 to 2.0 μm, and this steepness cannot be accounted for entirely by more effective myofilament overlap, as it is in skeletal muscle. The active length-tension relation of skeletal muscle (see Fig. 4.12 ) is obtained with constant levels of contractile activation, produced by tetanic stimulation, over the whole range of sarcomere lengths. Cardiac muscle, however, cannot be tetanized, and in cardiac muscle the level of contractile activation increases significantly over sarcomere lengths of 1.8 to 2.0 μm, thus accounting for the steep rise in active force. One mechanism not present to the same extent in skeletal muscle is that stretch of cardiac cells enhances the affinity of troponin C for Ca ⁺⁺ . Thus troponin C binds a greater amount of Ca ⁺⁺ and forms more crossbridges. The mechanism responsible for this greater affinity of troponin C for Ca ⁺⁺ remains to be determined. One concept is that the thick and thin filaments are brought closer to each other as the diameter of the muscle fiber narrows during stretch because the cell maintains constant volume. The protein, titin , may help in this process, in that it forms a scaffold that bonds actin and myosin filaments. Finally, another feature that differs from that of skeletal muscle is that the amount of Ca ⁺⁺ released from the SR in cardiac muscle increases with increasing sarcomere length. This is a time-dependent phenomenon, developing slowly over many beats, after the sarcomere length has been increased. Thus three cellular mechanisms contribute to the length dependence of cardiac muscle contraction from 1.8 to 2.2 μm: (1) changes in myofilament overlap, similar to those in skeletal muscle; (2) increased activation as a result of greater chemical affinity of troponin C for Ca ⁺⁺ ; and (3) increased activation as a result of greater release of Ca ⁺⁺ from the SR.

Developed force of cardiac muscle is less than the maximal value when the sarcomeres are stretched beyond the optimal length because the myofilaments overlap less and hence reduce crossbridge cycling. At very short sarcomere lengths, the thin filaments overlap each other in the central region of the sarcomere. This double overlap of the thin filaments diminishes contractile force.

In summary, the passive and active length–tension relations of cardiac muscle (see Fig. 4.11B ) arise from the mechanisms discussed previously and, in the whole heart, are reflected in the relationship between volume of the heart and its actively developed pressure, as discussed later.

Afterload Determines the Velocity of Cardiac Muscle Shortening

A strip of cardiac muscle, and the intact heart, also experiences an additional load (force) against which it must contract after it is activated ( Fig. 4.13 ). This load, known as afterload, determines the velocity with which the muscle can shorten. In the intact heart, this situation represents left ventricular ejection into the aorta. During ejection, the afterload is represented by the impedance due to aortic and intraventricular pressures, which are virtually equal to each other. Thus the afterload is the stress applied to the ventricle during ejection of blood.

The effects of afterload may be examined in experiments (see Fig. 4.13 ) similar to those for preload. If the afterload is such that the muscle can generate enough force to lift the load, then the muscle contracts isometrically until it generates enough force to lift the afterload, after which it can begin to shorten. The velocity of shortening is maximal ( V ₀ ) for no afterload and decreases monotonically to zero when the force (load) is too great for the muscle to lift at all (i.e., an isometric contraction). Norepinephrine increases the velocity of shortening at every level of afterload.

Ventricular Systole