Basic physiology: William Harvey recognized at the beginning of the 17th century that the heart pumps the blood through the whole body. The heart consists of four chambers, two atria that receive the blood and the two ventricles that pump the blood. The venous blood enters the heart via the right atrium, flows into the right ventricle and is pumped by the right ventricle through the lungs to pick up O2 and lose CO2. The rejuvenated blood enters the left atrium and delivers O2 to the tissues by the pumping action of the left ventricle (Fig. H1).

Fig. H1. Scheme of the heart compartments and the direction of the blood flow during diastole. Note the pulmonary artery on the top of the right ventricle and the aorta on the top of the left ventricle. The valves separating the atria from the ventricles are not shown.

Alternating contractions and relaxations of the heart muscle, called myocardium, causes the pumping of the heart. There is a pacemaker in the right atrium that generates electrical impulses causing the atria to contract and thereby forcing blood into the ventricles. Following contraction (systole) the ventricles relax (diastole); the entire process is called the cardiac cycle. Normal human heart beats about 70-times per minute at rest. The rate of heart beat increases during exercise, emotional excitement and fever, and decreases during sleep.

Ultrastructure: Cardiac muscle is composed of interconnected mono-nucleated cells. The cells are imbedded in a weave of collagen. The ultrastructure of the heart contains a large number of myofibrils, striated like in skeletal muscle. A large fraction of the cell volume is occupied by mitochondria, which synthesize ATP to supply energy for the constantly working heart muscle. Myofibrils and mitochondria occupy about 85% of the heart cell volume, the rest contains the sarcolemma, T-tubules, sarcoplasmic reticulum, and specialized structures such as the intercalated disk, which connects adjacent heart cells (cardiomyocytes), and gap junction or nexus which makes contact between the plasma membranes of adjacent heart cells (Fig. H2).

Fig. H2. Electron micrograph of cardiac muscle. (Courtesy of Dr. Helen Rarick)

Contractile Proteins

Myosin. Cardiac myosin is composed of two heavy chains (HCs) and four light chains (LCs). The ventricles contain only two types of light chains (skeletal muscle myosin possess three) with estimated molecular mass of 19,000 dalton (regulatory light chain, RLC) and 27,000 dalton (essential light chain, ELC). The mass of entire cardiac myosin is about 480,000 and its length is approximately 1,700 Å (Katz 1992), similar to these parameters in skeletal muscle myosin.(For structural organization see Figure M1)

The multigene families of HCs and LCs generate different isoforms that occur at various stages of heart development. Two HC isoforms are known as a- and b-isoforms. First it was thought that the functional properties of heart muscle are determined by the LC composition, but it turned out that HCs determine the myosin ATPase activity in vitro and the shortening velocity in the intact heart (Katz, 1992).

In the atria there are two myosin isoforms, A1 and A2, with high and low ATPase activity, respectively, whereas in the ventricles there are three myosin isoforms, composed of either homodimer or heterodimer HCs, V1 (a-a), V2 (a-b), and V3 (b-b), with high, intermediate, and low ATPase, respectively. A comparative study on the various ATPase activities of rabbit heart and skeletal muscle myosins showed that under all conditions the activities of the skeletal source are higher (Bárány et al., 1964).

The atria and the ventricles contain different LC isoforms. The atrial LCs are also found in developing heart and fast skeletal muscle, and in adult slow skeletal muscle. The 19,000-dalton heart LC is phosphorylated and possibly participates in the regulation of heart contraction (Kopp and Bárány, 1979).

Actin: Heart actin has not been studied in detail. It is generally believed that heart and skeletal actin have a very similar structure and their biological properties are also similar. That is, actin in the thin filaments is built of monomers, it binds TM and TN (see Fig. A6), upon contractile stimulus it binds to myosin and it activates myosin ATPase.

Regulatory Proteins

TN-C. The cardiac muscle TN-C (cTN-C) differs from fast skeletal muscle TN-C that it contains only one Ca2+-binding site in the N-terminal domain of the protein. The neighboring site, at the N-terminal does not contain aspartic acid, a prerequisite for coordination of Ca2+. This site is called site 1, whereas the Ca2+-binding site is called site 2 of cTN-C.

TN-I: The cardiac TN-I (cTN-I) differs from the fast skeletal muscle TN-I by containing an N-terminal extension of 32 amino acid residues (Fig. H3).


Fig. H3. Comparison of the overall structure of cardiac muscleTN-I with that of skeletal muscle TN-I. The shaded areas correspond to homologous regions in the structures (From Perry 1996)..

This extension has two adjacent serine residues, No. 22 and 23 in the sequence. Solaro et al. (1976) discovered that TN-I is phosphorylated in perfused rabbit heart stimulated by adrenaline. It was shown later (Mittmann et al.,1990; 1992) that both serines at positions 22 and 23 of rabbit cardiac TN-I can be phosphorylated by cyclic AMP-dependent protein kinase (PKA). Since PKA is activated by adrenaline in the beating heart it appears that PKA is responsible for the diphosphorylation of TN-I in the heart.

Early studies have established that TN-I phosphorylation decreases the Ca2+-sensitivity of cardiac myofibril MgATPase (Ray and England, 1976; Solaro et al., 1976), i.e. the Ca2+ concentration for 50% ATPase activity increases. The motif of two adjacent serine residues was found in hearts from various mammals suggesting that modulation of Ca2+-sensitivity by phospho-TN-I is characteristic for heart muscle. The mechanism of this effect is of interest. Cardiac muscle contraction is initiated by the binding of Ca2+ to site 2 of TN-C as site 1 does not function as Ca2+-binding site (see above). NMR, fluorescence resonance energy transfer, and mutation studies indicate that the N-terminal part of TN-I combines with TN-C. Upon phosphorylation of TN-I, the site 1 of TN-C undergoes a conformational exchange consistent with an equilibrium between closed and opened forms of TN-C (Gaponenko et al., 1999). In addition, TN-I phosphorylation changes the binding of Ca2+ to TN-C, the structure of TN-I, and the cooperative binding of TN-I to actin-TM (Solaro and Van Eyk, 1996). Previously, phosphorylation has been shown to modulate cardiac function by reducing the Ca2+ affinity for the N-terminal regulatory site of cTN-C (Solaro, 1986). Thus, TN-I phosphorylation is a unique property of the myocardium that plays a key role in cardiac function.

Recently, fluorescence resonance energy transfer was used (Dong et al., 2001) to investigate the global conformation of the inhibitory region of a full-length TN-I mutant from cardiac muscle in the unbound state and in reconstituted complexes with the other cardiac TN subunits. The mutant contained a single tryptophan residue at the position 129 which was used as an energy transfer donor, and a single cysteine residue at the position 152 labeled with IAEDANS as an energy acceptor. The distance between the donor and acceptor sites was found to be 19.4 Å and it was insensitive to reconstitution of cTN-I with cTN-T, cTN-C, or cTN-C plus cTN-T, in the absence of bound regulatory Ca2+ in cTN-C. A large increase in the Trp129-Cys152 distance was observed upon saturation of the Ca2+ regulatory site of cTN-C in the complexes. This increase suggests an extended conformation of the inhibitory region in the interface between cTN-C and cTN-I in the holo cardiac troponin, which may pull away the inhibitory region of cTN-I from actin upon Ca2+activation in cardiac muscle.

TN-T: As skeletal TN-T, cardiac TN-T (cTN-T) also has several isoforms (McAuliffe et al., 1990). Two cTN-T isoforms have been identified in adult beef heart, which show differences in their sequence and activation of the actinS1 ATPase. Five isoforms were found in rabbit heart and two in rat heart. During development of rabbit heart, there are shifts in the isotype population of cTN-T and these are related to the differences in the Ca2+ regulation between neonate and adult hearts.

Mutations between residues 92 and 110 of cTN-T impair its TM-dependent functions (Palm et al., 2001).

TM: In skeletal muscle two isoforms of TM, a and b (each under different genetic control) are expressed. In contrast, in the heart only the a-form of TM is expressed. However, using transgenic approaches mice could be produced which overexpressed b-TM in the heart. Novel functions of this TM isoform were detected (Palmiter et al.,1996). Thus, the cardiac myofilaments, containing b-TM demonstrated an increase in the activation of the thin filament by strongly bound cross-bridges, an increase in Ca2+ sensitivity of steady state force, and a decrease in the rightward shift of the Ca2+-force relation induced by cAMP-dependent phosphorylation. These data indicate that switching of TM isoform has a major effect on heart myofilament activity.

Movement of the regulatory proteins in systole versus diastole. Fig. H4 depicts the position of TM and the TN components in the thin filaments. In diastole, TM is fixed in the groove of the actin double helix by TN-T and the C -terminus of TN-I. The position of the TM is such that the myosin cross-bridges (MHC, ELC, RLC) can not react with actin. The binding of Ca2+ to TN-C is the signal for systole, the N-terminus of TN-C interacts with the C-terminus of TN-I. Now TM is free to move on the thin filament removing the steric hindrance of the actin-cross-bridge reaction and systole ensues.

Fig. H4. Illustration of the movement of the regulatory proteins in systole versus diastole (Courtesy of Dr. Helen Rarick). For details see the text.

In summary, cardiac contraction is a series of interactions between Ca2+, the regulatory proteins, and the actomyosin system. In the resting muscle, at low intracellular free Ca2+concentration, the TN-TM complex inhibits the actin-myosin combination and with an increase in the myoplasmic Ca2+ the inhibition is released. The Ca2+ signaling process starts with the binding of Ca2+ to a single regulatory site of TN-C and by a tight binding of TN-C to TN-I. The signal is transmitted by TN and TM to actin in the thin filament. The final step is the combination of actin with myosin.


Displacement of endogenous TN in skinned fibers with TN mutants: A very sensitive method for mapping the functional domains of TN components is the replacement of native TN in the fibers with modified TN and then assaying force development or Ca2+-sensitivity of the modified fibers. In principle, the fibers are briefly treated with 1% Triton X-100 to remove the sarcolemma and subsequently washed to remove the Triton. The fibers are exposed to 10-20-fold excess of exogenous TN, over the endogenous TN, in a medium containing 250 mM KCl. Finally, unbound TN is removed by washings of the fibers. In the past, most of the replacement studies were performed with skeletal muscle fibers, recently a method for exchanging the TN subunits in cardiac fibers was published (Chandra et al., 1999). The skinned rat cardiac fiber bundles remained relaxed through much of the extraction/reconstitution procedure. The fibers were treated with a mixture of cTN-T-cTN-I to displace the endogenous TN; 70-80% of the endogenous TN subunits were removed. After reconstitution with cTN-C the Ca2+-dependence of the force development by the fibers was restored to an extent of 80-85%.

Reconstitution of a modified TN can also be carried out at the level of myofibrils and the Mg2+-ATPase activity of the modified fibrils can be measured as a function of pCa (Rarick et al., 1997).

Purification of cardiac myofibrils is important for studying the interaction of the troponin components with each other, with tropomyosin and actin. Myofibrils purified by conventional methods are contaminated with mitochondrial, sarcolemmal and sarcoplasmic reticulum membranes. Treatment of these myofibrils by 1% Triton X-100 readily removes the contaminants (Solaro et al., 1971). The MgATPase activity of the purified myofibrils corresponds to that of cardiac actomyosin and they exhibit the normal high Ca2+-sensitivity.

Gel elctrophoresis of the regulatory proteins: In our laboratory, 10% polyacrylamide gels containing 1% SDS, 0.1 M Na-phosphate, pH 7.0 and 8.0 M urea are used for separation of TM, TN-T and TN-I (Fig. H5). Under these conditions TM (zone A, 48-kDa) migrates behind actin, TN-T (zone B, 38-kDa) migrates in front of actin, TN-I (zones C and D, 30- and 29 kDa) splits into two components. Zones E and F, correspond to the 27- and 19-kDa myosin LCs. TN-C migrates in front of the 19-kDa LC, it is not visible because it does not stain with Coomassie blue.


Fig. H5. Separation of rat heart myofibril proteins by gel electrophoresis (From Kopp and Bárány, 1979). Gel 1, myofibrils; gel 2, beef heart myosin; gel 3, beef heart troponin; and gel 4, beef heart TM. For other details see the text.

Literature: A detailed review on the interaction of the TN complex, TM, and actin in cardiac thin filaments is available (Tobacman, 1996)

Regulation of Ca2+ Flow

Sarcoplasmic Reticulum

Ca2+ transport into the sarcoplasmic reticulum (SR) occurs via the action of the SR Ca2+ pump. As in skeletal muscle, 1 molecule of ATP has to be hydrolyzed per 2 molecules of Ca2+ that are pumped against a large concentration gradient into the lumen of the SR. The SR Ca2+-ATPase, called sarco(endo)plasmic reticulum Ca-ATPase (SERCA), is regulated by phospholamban (described below). Ca2+ is released from SR through a Ca2+-sensitive SR Ca2+ release channel. The channel tightly binds ryanodine and, therefore, it is also referred to as the ryanodine receptor (RYR).

Ca2+ induced Ca2+ release (CICR) CICR is specific for the heart. The small amount of Ca2+ that enters the cell through voltage dependent plasmalemmal Ca2+ channels (which open in response to the action potential) causes a much larger amount of Ca2+ to be released from within the SR.

Calsequestrin is a Ca2+ binding protein that is located within the lumen of SR and is primarily responsible for Ca2+ storage within the SR.

Phospholamban (PLB): It is a pentamer made up of five identical subunits, each 6,000 dalton (52 amino acid residues). PLB is found in cardiac, slow skeletal and smooth muscle but it is absent in fast skeletal muscle. The protein is associated with the Ca2+-pump ATPase in the membrane of the sarcoplasmic reticulum. The flexible N-terminus on which the phosphorylation sites are located extends out into the cytoplasm of the cardiac muscle cell. The phosphorylation site at serine 16 is a substrate for PKA, whereas threonine 17 is phosphorylated by a Ca2+-calmodulin dependent protein kinase. Phosphorylation of PLB by PKA increases the rate of Ca2+ transport and the Ca2+-sensitivity of the Ca2+-pump and thereby facilitates relaxation in heart exposed to b-adrenergic agonists (Katz, 1992; Perry, 1996). Phosphorylation of PLB by a Ca2+-calmodulin dependent protein kinase also stimulates Ca2+-uptake in vitro, but its physiological significance is not known.

Research on the physiological significance of PLB reached an unexpected turn when a PLB deficient mice was generated, the "PLB knockout (KO) mouse". Surprisingly, there were no detrimental effects in the performance of such animals or in the function of their isolated heart. For instance, the basal contractility and the Ca2+-transient of myocytes isolated from PLB deficient hearts were enhanced compared with cells isolated from wild type animals. Furthermore, the contractility of PLB-deficient myocytes could be further enhanced by the b-adrenergic agonist, isoproterenol. These results demonstrate that in the absence of PLB, there are mechanisms available in the heart to adjust its activity, and that phosphorylation of sites other than PLB may play an important role in regulation of contraction-relaxation dynamics of heart responding to b-adrenergic stimulation (Wolska et al.,1996)

Factors controlling the Ca2+ release from SR:

Ryanodine (a plant derived alkaloid) is a very effective drug that alters the SR Ca2+ release channel.

Phospholamban phosphorylation by PKA.

Thapsigargin and cyclopiazonic acid (CPA) that block the Ca2+ pump.

Digitalis, a drug that inhibits the Na+/K+ pump leading to a small increase in intracellular Na+. This decreases the rate at which the Na+/Ca2+ exchanger extrudes Ca2+ from the cell and thus leads to enhanced loading of the SR.


Ca2+ enters the cardiac cell during the plateau phase of the action potential via the L-type Ca2+ channel. (The channel tightly binds the Ca2+ channel blocking agents of the dihydropyridine family). The sarcolemmal Na+/Ca2+ exchanger transports 3 Na+/Ca2+. The energy for this transport is indirectly derived from ATP hydrolysis via the sodium gradient that is established by the Na+/K+ pump. It is the major Ca2+ extrusion mechanism of the cardiac myocyte and may contribute significantly to myocardial relaxation. The sarcolemma also houses the Na+/K+-ATPase that transports 3 Na+ out and 2 K+ into the cell per molecule of ATP, and thus moves out one net charge per cycle. This is the key transporter that sets up the sarcolemmal ionic gradients for Na, K, and Ca, and consequently allows ion channels to function. The Na+ and K+ channels in the sarcolemma are involved in action potential generation. Fig.H10 (at the end of the chapter) illustrates the channels and the ion movements in the sarcolemma.

Ca2+ Sensitivity

Ca2+ is the central factor in myocardial contraction and the potential of a cardiac system to be activated by Ca2+ is characterized by its Ca2+ sensitivity. Originally, Ca2+ sensitivity was used to define the relationship between Ca2+ concentration and tension, but later the relationship was extended from tension to other parameters as well, e.g. myofibrillar ATPase activity or fluorescence intensity. Conventionally, Ca2+ sensitivity is illustrated by plotting the pCa against the selected parameter, expressed as percentage of the control value (Fig. H6).

Fig. H6. Graph for a pCa - activity relationship in a biological system. "A" and "B" represent the variations within the same system, e.g. animals of different ages.

The pCa curve can shift to the left "increased Ca2+ sensitivity" or to the right "decreased Ca2+ sensitivity". The extent of shift can be estimated from the difference of the pCa values at 50% activity. The shift may be small, 0.05 pCa, or large >1.0 pCa.

There are several factors, which influence the Ca2+ sensitivity of the myocardium. In case of the Force - pCa relationship the factors are:TN-I phosphorylation, b-tropomyosin, aging, acidosis, sarcomere length, temperature, ionic strength, caffeine, or other agents (Bers, 2001). It should be mentioned that most Force - pCa relationship were measured on cardiac myofilaments with their sarcolemma removed by Triton treatment, "skinned fibres"; the Ca2+ sensitivity of the skinned preparations may differ from those of intact heart ventricles.

Some authors attribute the differences in Ca2+ sensitivity among hearts of various animals, frog, guinea pig, rat, rabbit, or cow, to differences in their TN-C content. On the other hand, others feel that the Ca2+ sensitivity is not based on the single reaction between Ca2+ and TN-C but it rather reflects a series of reactions involved in the signal transduction initiated by Ca2+.

The level of intracellular Ca2+ plays a major role in the Ca2+ activation of the myofilament. Fig. H7 shows the factors establishing the Ca2+ level. Ca2+ enters the myoplasm through the Ca channels, it may trigger release of new Ca2+ from the SR or it may be stored in the SR. The intracellular Ca2+ can initiate contraction through the TN system. Excess Ca2+ is leaving the heart cell through the sarcolemma.

Fig. H7. Regulation of Ca2+ activation of the myofilament. (Courtesy of Dr. Helen Rarick)

Excitation-Contraction Coupling

Despite important difference between skeletal and cardiac muscle, the general scheme for excitation-contraction (E-C) is similar. Electrical excitation of the surface membrane leads to an action potential which propagates as a wave of depolarization along the surface and along the transverse (T) tubules. The depolarization of the T-tubule overlying the terminal cisternae of the SR induces the release of Ca2+ from SR. The Ca2+ released from SR then binds to TN-C which activates contraction. Cellular Ca2+ movement in the heart is somewhat complex because of the presence of Ca2+ channels and transport system in the sarcolemma.

There is a recurring theme that skeletal muscle contraction depends almost exclusively on Ca2+ released from SR with insignificant Ca2+ entry across the sarcolemma during a normal twitch. Cardiac muscle contraction, on the other hand, depends on both Ca2+ entry across the sarcolemma and Ca2+ release from the SR. There are notable differences in the ultrastructure: Skeletal muscle has an extensive and well organized SR network, abutting the narrow T-tubules. In contrast, the SR of cardiac muscle is rather sparse and less organized, and surrounded with T-tubules of much larger diameter. In addtion cardiac myocytes are only 0.02 nm thick, whereas the diameter of the skeletal muscle fibers goes up to 0.2 nm. Thus, a substance from the extracellular space reaches the center of the heart cell much faster than the center of the skeletal muscle cell. In general the structure of the cardiac cell is consistent with a larger role of the transsarcolemmal Ca2+ fluxes.

Major events in cardiac E-C coupling (courtesy of Dr.Pieter de Tombe):


Ca2+ induced Ca2+ release

Activation of contractile proteins

Ca2+ reuptake into the SR and Ca2+ extrusion leading to relaxation

Biochemistry of Starling's Law

The Starling law describes an enhancement of contractile function of the heart resulting from the increased end-diastolic ventricular volume and consequently from an increase in muscle length. The Starling law also applies to skeletal muscle but in cardiac muscle it is much more pronounced. The simplest explanation of the phenomenon is based on the constant volume principle, i.e. the increased muscle length requires a decrease in the interfilament space in order to keep the volume of the muscle cell constant. X-ray diffraction studies verified this assumption (Irving et al., 2000). Accurate measurements of interfilament spacing, by synchrotron X-ray diffraction, as a function of sarcomere length, using skinned and intact rat trabecules demonstrated that the lattice spacing was decreased as sarcomere length increased. Thus, the Starling law can be explained by the enhanced actin and myosin interaction as the result of moving the actin and myosin filaments closer to each other at the longer muscle length.

The Starling law is also characterized by an increase in Ca2+ sensitivity of the cardiac myofilaments as the sarcomere length increases (Fig, H8.).

Fig. H8. Relation between Ca2+ concentration and tension generation of cardiac myofilaments at long and short sarcomere length(SL) (From Solaro, 1999).

At longer sarcomere length the distance between thick and thin filaments decreases and hence the length of the diffusion pathway for Ca2+, in the interfilament space, to reach TN-C decreases. One can assume that saturation of TN-C with Ca2+ and subsequent activation of the thin filaments is easier and faster at smaller interfilament spacing than at the larger spacing. However, the explanation is more complex because tension development induced by Ca2+ is not a linear but a cooperative activation of the actin-myosin combination.

Fig. H9 illustrates a current method to measure force-length relation in cardiac muscle. A small strip of cardiac muscle is mounted in an experimental setup. Sarcomere length is measured by laser diffraction techniques. Force is measured by a sensitive force transducer. Muscle length is controlled by a high speed device.

Fig.H9. Force-length measurement with small heart strips (Courtesy of Dr. Pieter de Tombe).


The energy the heart uses to perform pumping the blood is generated through the hydrolysis of ATP to ADP and Pi. ATP is constantly generated by the mitochondria that are abundant in heart muscle cells. Since the outer mitochondrial membrane is impermeable to adenine nucleotides there is need for "energy carriers" to transport the energy into the cytosol. This is achieved by the phosphorylcreatine (PCr) shuttle (Bessman and Geiger, 1981), that is excess ATP is transformed to PCr within the mitochondrial inner membrane through creatine kinase isoforms, located in the mitochondria. The PCr formed diffuses into the cytoplasm to saturate the myofibrillar water. When ATP is hydrolyzed by actomyosin, during heart beat, the ADP formed will be immediately regenerated by PCr with aid of specific creatine kinase isoforms..

In addition to the contractile apparatus, ATP is also used by the Ca2+-ATPase and Na+/K+-ATPase of the sarcolemma, by the Ca2+-ATPase of SR to store Ca2+, and by biosynthetic processes.

About 90% of the ATP is synthesized by oxidative phosphorylation in the mitochondria and about 10% by glycolysis, that take place in the cytosol. Mitochondria are strictly dependent on O2, they mainly oxidize fatty acids (note: of all the food we eat fat has the highest calorie value) and pyruvate, arising from the glycolysis of glucose.

Since PCr plays an important role in cardiac energetics, creatine depletion and creatine supplementation studies were carried out in order to gain more insight into muscle energetics. Feeding rats with the creatine analogue b-guanidinopropionate (b-GP) reduced myocardial PCr and Cr by about 80%, the velocity of the creatine kinase reaction decreased by 90%, but the level of ATP remained unchanged (Neubauer et al., 1999). The same biochemical alterations were found in isolated rat hearts perfused with b-GP; this was accompanied by reduced contractile performance in vitro. However, in intact rats only a minimal functional impairment was observed. Thus, in intact rat heart cardiac and/or humoral compensatory mechanisms are sufficient to maintain normal hemodynamics in spite of the greatly reduced PCr concentration. The same conclusion could be drawn from studies on creatine kinase knock-out animals, which exhibited normal muscle activity suggesting that neither creatine kinase nor PCr are central to cellular energy metabolism. However, both creatine kinase knock out and creatine analogue fed animals showed marked myofibrillar and mitochondrial remodeling (suggesting energy transduction is altered), and the impairment of muscle function during near maximal, rather than submaximal contraction.

Five days high dose creatine feeding enhanced creatine disposal and glycogen storage in rat skeletal muscles (Op't et al., 2001). The creatine and glycogen response was markedly greater in oxidative than in glycolytic muscles. This investigation contributes to the understanding of how the increased use of creatine by athletes, as a dietary supplement, improves their physical performance.

Summary: Fig.H10 shows the factors which determine contractility in the heart.

Fig. H10. An overview of the chemical events taking place in the working heart.(Courtesy of Dr. Pieter de Tombe).

The movements of Na+ and K+ determine the electrical properties of the heart membrane. The Ca2+ homeostasis is established by the Ca2+ channel which lets the Ca2+ in and the Ca2+ pump and Na+/Ca2+ exchanger which remove the excess Ca2+ from the heart cell. The intracellular Ca2+ is partially stored in the SR, but its main function is to activate the sarcomere to produce force and shortening. The energy cost for the external mechanical work and Ca2+ storage is covered by ATP, produced by the mitochondrion. The mitochondria burn glucose, acetate and other fatty acids to CO2 and H2O, which leave the cell by diffusion.

Suggested readings: The following books (Bers, 2001; Katz, 1992; Solaro, 1986) and reviews (Solaro, 1999; Janssen, 1997; Solaro and Van Eyk,1996; Tobacman, 1996) can help to increase knowledge in the biochemistry of cardiac contractility.


Bárány, M., Gaetjens, E., Bárány, K. and Karp, E. (1964). Comparative studies of rabbit cardiac and skeletal myosins. Arch. Biochem. Biophys. 106, 280-293.

Bers, D.M. (2001). Excitation-contraction coupling and cardiac contractile force. Kulwer Academic Publishers, Dordrecht.

Bessman, S. P. and Geiger, P.J. (1981). Transport of energy in muscle: the phosphoryl creatine shuttle. Science, 211, 448-452.

Chandra, M., Kim, J.J., and Solaro, R. (1999). An improved method for exchanging troponin subunits in detergent skinned rat cardiac fiber bundles. Biochim. Biophys. Res. Commun. 263, 219-223.

Dong, W-J., Xing, J., Robinson, J.M., and Cheung, H.C. (1991). Ca2+ induces an extended conformation of the inhibitory region of troponin I in cardiac muscle troponin. J. Mol. Biol. 314,  51-61.

Gaponenko, V., Abusamhadneh, E., Abbot, M.B., Finley, N., Gasmi-Seabrook, G., Solaro, R.J., Rance, M., and Rosevear, P.R. (1999). Effects of troponin I phosphorylation on conformational exchange in the regulatory domain of cardiac troponin C. J.Biol. Chem. 274, 16881-16884.

Greenhaff, P.L. (2001). The creatine-phosphocreatine system: there 's more than one song in its repertoire.J. Physiol. 537, 657-657.

Irving, T.C., Konhilas, J., Perry, D., Fischetti, R., and De Tombe, P.P. (2000). Myofilament lattice spacing as a function of sarcomere length in isolated rat myocardium. Am. J. Physiol. 279, H2568-H2573.

Janssen, P.M.L. (1997). Determinants of contraction and relaxation in mammalian myocardium: Effects of calcium and sarcomere length. Ph.D. Thesis, University of Utrecht, The Netherlands, ISBN 90-393-1120-X

Katz, A. M. (1992). Physiology of the heart. Raven Press, New York.

Kopp, S.J., and Bárány, M. (1979). Phosphorylation of the 19,000-Dalton light chain of myosin in perfused rat heart under the Influence of negative and positive inotropic agents. J. Biol. Chem. 254, 12007-12012.

McAuliffe, J.J., Gao, L., and Solaro, R.J. (1990). Changes in myofibrillar activation and troponin C Ca2+ binding associated with troponin T isoform switching in developing rabbit heart. Circulation Research 66, 1204-1216.

Mittmann, K., Jaquet, K., and Heilmeyer Jr., L.M.G. (1990). A common motif of two adjacent phosphoserine in bovine, rabbit, and human cardiac troponin I. FEBS Letters, 273, 41-45.

Mittmann, K., Jaquet, K., and Heilmeyer Jr., L.M.G. (1992). Ordered phosphorylation of a duplicated minimal recognition motif for cAMP -dependent porotein kinase present in cardiac troponin I. FEBS Letters, 302, 133-137.

Neubauer, S., Hu, K., Horn, M., Remkes, H., Hoffmann, K. D., Schmidt, C., Schmidt, T.J., Schnakerz, K., and Ertl, G. (1999). Functional and energetic consequences of chronic myocardial creatine depletion by b-guanidinopropionate in perfused hearts and in intact rats. J. Mol. Cell. Cardiol. 31, 1845-855.

Op't, E.B., Richter, E.A., Henquin, J.-C., Kiens, B., and Hespel, P. (2001). Effect of creatine supplementation on creatine and glycogen content in rat skeletal muscle. Acta Physiologica Scandinavica, 171, 169-176.

Palm, T., Graboski, S., Hitchcock-DeGregori, S.E.,. and Greenfield, N.J. (2001). Disease-causing mutations in cardiac troponin-T: Identification of a critical tropomyosin-binding region. Biophys. J., 81, 2827-2837.

Palmiter, K.A., Kitada, Y., Muthuchamy, M., Wieczorek, D.F., and Solaro, R.J. (1996). Exchange of b- for a-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+, strong cross-bridge binding, and protein phosphorylation. J. Biol. Chem. 271, 11611-1164.

Perry, S.V. (1996). Molecular mechanisms in striated muscle. Cambridge University Press, Cambridge, UK.

Rarick, H.M., Tu, X-H., Solaro, R.J., and Martin, A.F. (1997). The C terminus of cardiac troponin I is essential for full inhibitory activity and Ca2+ sensitivity of rat myofibrils. J. Biol. Chem., 272, 26887-26892.

Ray, K.P., and England, P.J. (1976). Phosphorylation of the inhibitory subunit of troponin and its effect on the calcium dependence of cardiac myofibril adenosinetriphosphatase. FEBS Letters, 70, 11-16.

Solaro, R.J., Pang, D.C., and Briggs, N. (1971). The purification of cardiac myofibrils with Triton X-100. Biochim. Biophys. Acta, 245, 259-262.

Solaro, R.J., Moir, A.J.G., and Perry S.V. (1976). Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart. Nature, 262, 615-617.

Solaro, R.J. (1986) In Protein Phosphorylation in the Heart Muscle (R.J. Solaro, Ed.) pp. 129-156, CRC Press Inc., Boca Raton, FL.

Solaro, R..J. and Van Eyk, J. (1996) Altered interactions among thin filament proteins modulate cardiac function. J. Mol. Cell. Cardiol. 28, 217-230.

Solaro, R.J. (1999). Integration of myofilament response to Ca2+ with cardiac pump regulation and pump dynamics. Advances in Physiology Education, 22, S155-S163.

Tobacman, L.S. (1996). Thin filament-mediated regulation of cardiac contraction. Annu. Rev. Physiol. 58, 447-481.

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