Structure

The anatomic design of the heart determines many of its major mechanical capabilities and limitations. The annuli of the cardiac valves, the aortic and pulmonary arterial roots, the central fibrous body, and the left and right fibrous trigones form the skeletal base of the heart. This flexible but very strong cartilaginous structure is located at the superior (termed basal in opposition to the left ventricular [LV] apex) aspect of the heart; provides support for the translucent, macroscopically avascular valves; resists the forces of developed pressure and blood flow within the chambers; and provides a site of insertion for superficial subepicardial muscle.¹ Most of the atrial and ventricular muscle is not directly connected to this central fibrous skeleton, but instead arises from and inserts within adjacent surrounding myocardium consistent with the well-known embryologic derivation of the heart from an expanded arterial blood vessel.² An interstitial collagen fiber network (composed of thick type I collagen cross-linked with thin type III collagen) also provides important structural support to the myocardium. The protein elastin is closely associated with this collagen matrix, thereby imparting additional flexibility and elasticity to the heart without compromising its strength. In contrast with William Harvey’s original assertion,³ atrial and ventricular myocardium cannot be separated into distinct bands or layers* using an “unwinding” dissection technique^4,5 and, instead, is a continuum of interconnecting cardiac muscle fibers. The left and right atria (LA and RA, respectively) are composed of two relatively thin, orthogonally oriented layers of myocardium. The right ventricular (RV) and, to an even greater extent, the LV walls are thicker (approximately 5 and 10 mm, respectively) than those of the atria and consist of three muscle layers: interdigitating deep sinospiral, the superficial sinospiral, and the superficial bulbospiral. Well-ordered, differential alterations in fiber angle extending from the endocardium to the epicardium are especially apparent in ventricular myocardium and are spatially conserved despite the substantial alterations in wall thickness that occur with contraction and relaxation during the cardiac cycle (Figure 5-1).⁶ Subendocardial and subepicardial muscle fibers of the LV follow perpendicular, oblique, and helical routes from the base to the apex, but orientation of these interdigitating sheets of cardiac muscle also reverses direction at approximately the midpoint of the LV. Thus, LV fiber architecture resembles a flattened “figure of eight” (Figure 5-2). Contraction of obliquely arranged subepicardial and subendocardial fibers causes LV chamber shortening along its longitudinal axis and is accompanied by a characteristic “twisting” action that increases the magnitude of force generated by the LV during systole above that produced by basal-apical muscle fiber shortening alone. Indeed, a transition of this primarily helical geometry into a more spherical configuration has been proposed to directly contribute to the reduction in ejection fraction (EF) observed during evolving HF.⁷ Elastic recoil of this systolic “wringing” motion during LV relaxation is also an important determinant of diastolic suction, a critical factor that preserves LV filling during profound hypovolemia and strenuous exercise.^8,9 In contrast with the subepicardial and subendocardial layers, most fibers within the midmyocardium are circumferentially oriented around the diameter of the LV cavity, and their contraction reduces chamber diameter.

Figure 5-1 Sequence of photomicrographs depicting myocardial fiber angles at successive sections from the endocardial (top) to the epicardial surface (bottom) through the thickness of the left ventricular anterior wall. Note the transition in myocardial fiber orientation relative to wall thickness from the subendocardium (perpendicular) to the midmyocardium (parallel). A mirror image transition in fiber orientation is observed from the midmyocardium to the subepicardium.

Katz AM: Physiology of the Heart, 3rd ed. Lippincott Williams and Wilkins, 2001.

Figure 5-2 Photograph (A) and schematic illustration (B) depicting the spiral orientation of fiber continuity in the left ventricle (LV). The photograph in A demonstrates a dissection of the human LV anterior and lateral walls showing spiral cardiac muscle bundles sweeping from the base to the apex. This helical orientation is schematically represented in B. Another photograph (C) shows a dissection of endocardial fiber orientation at the left ventricular apex and also demonstrates this spiral fiber structure.

Katz AM: Physiology of the Heart, 3rd ed. Lippincott Williams and Wilkins, 2001.

Valves

Two pairs of valves assure unidirectional blood flow through the right and left sides of the heart. The pulmonic and aortic valves are trileaflet structures located at RV and LV outlets, respectively, and operate passively with changes in hydraulic pressure gradients. The pulmonic valve leaflets are identified by their simple anatomic positions (right, left, and anterior), whereas the name of each aortic valve leaflet is derived from the presence or absence of an adjacent coronary artery ostium (right coronary cusp located adjacent to the right coronary artery [RCA] ostium, left coronary cusp located adjacent to the left main coronary artery ostium, and noncoronary cusp without a coronary ostium). The pulmonic and aortic valves open as a consequence of RV and LV ejection, respectively. The effective orifice area of each of these valves during maximal systolic blood flow is only modestly less than total cross-sectional area of the respective valve annulus. The proximal aortic root contains dilated segments, known as the sinuses of Valsalva, located immediately behind each leaflet. The sinuses of Valsalva prevent the aortic valve leaflets from closely approaching or adhering to the aortic wall by facilitating the formation of eddy currents of blood flow during ejection, thereby preventing the right and left coronary leaflets from occluding their respective coronary ostia. The eddy currents within the sinuses of Valsalva also assist with aortic valve closure at the end of ejection by assuring that the leaflets remain fully mobile during early diastole.¹⁴ In addition, the normal velocity of blood flow through the aortic valve (approximately 1.0 m/sec) creates vortices of flow between the aortic valve leaflets and the sinuses of Valsalva that serve to further prevent leaflet-aortic wall contact.¹⁵ In contrast with the aortic root, the proximal pulmonary artery does not contain sinuses.

The thin, flexible, and very strong mitral valve separates the LA from the LV. The mitral valve is a saddle-shaped structure containing two leaflets, identified as anterior and posterior on the basis of their anatomic location. The valve leaflets coapt in the middle of the annulus in a simple central curve in which the anterior mitral leaflet forms the convex border. The anterior mitral leaflet is oval and occupies a greater central diameter across the annulus, whereas the posterior mitral leaflet is crescent shaped and extends farther around the annular circumference. As a result, the cross-sectional area of each leaflet is similar. The leaflets are physically joined at anterior-lateral and posterior-medial commissures that are located superior to corresponding papillary muscles. The leaflets thicken slightly along the line of coaptation. The pressure gradient between the LA and LV chambers near the end of LV relaxation combined with LV mechanical recoil cause opening of the mitral valve, whereas retrograde blood flow toward the valve during LV contraction forces the previously open valve leaflets in a superior direction and produces coaptation. Thin fibrous threads, termed chordae tendineae, attach to the papillary muscles and prevent inversion of the valve leaflets during contraction. Primary and secondary chordae tendineae insert into the valve edges and the clear and rough zones of the valve bodies (located approximately one third of the distance between the valve edge and the annulus), respectively, of the leaflets. Tertiary chordae tendineae extend from the posteromedial papillary muscle and insert into the posterior mitral leaflet or the adjacent myocardium near the annulus. Each papillary muscle is an outpouching of subendocardial myocardium that provides chordae tendineae to both mitral valve leaflets and contracts synchronously with the main LV. Papillary muscle contraction tightens the chordae tendineae, thereby inhibiting excessive leaflet motion beyond the normal coaptation zone and preventing regurgitation of blood into the LA.¹⁶ The mitral annular circumference also decreases modestly during LV contraction through a sphincter-like action of the surrounding subepicardial myocardium that reduces the total orifice area and assists in valve closure.¹⁷ The importance of the functional integrity of the mitral valve apparatus to overall cardiac performance cannot be overemphasized. The apparatus not only assures unidirectional blood flow from the LA to the LV by preventing regurgitant flow into the LA and proximal pulmonary venous circulation, but also contributes to LV systolic function through papillary muscle contributions to LV apical posteromedial and anterolateral contraction. For example, loss of native chordae tendinea-papillary muscle attachments associated with mitral valve replacement is invariably associated with a modest decrease in global LV contractile function. Similarly, papillary muscle ischemia or infarction frequently causes mitral regurgitation and also may contribute to the development of LV systolic dysfunction.

The anterior (also known as anterosuperior), posterior (inferior or mural), and septal (medial) leaflets and their corresponding chordae tendineae and papillary muscles comprise the tricuspid valve that regulates blood flow from the RA to the RV. The anterior and septal leaflets are usually larger than the posterior leaflet. The presence of a septal papillary muscle distinguishes the morphologic RV from the LV in patients with certain forms of congenital heart disease (e.g., transposition of the great vessels). A lateral band of myocardium, known as the moderator band, connects the apical anterior and septal papillary muscles, and demarcates the RV inflow and outflow tracts. Relatively fine trabeculations characterize the LV subendocardial surface, but the RV contains a large quantity of coarse trabeculae carneae throughout the chamber. The reasons for this difference in trabeculation are unknown. Unlike the mitral valve, the tricuspid valve does not have a clearly defined collagenous annulus. Instead, the RA myocardium is separated from the RV by the AV groove that lies immediately above, may fold into the origin of the tricuspid leaflets, and contains the proximal portion of the RCA.

Blood Supply

Blood flow to the heart is supplied by the left anterior descending, left circumflex, and right coronary arteries (LAD, LCCA, and RCA, respectively). Most of the blood flow to the LV occurs in diastole when aortic blood pressure exceeds the LV chamber pressure, thereby establishing a positive-pressure gradient in each coronary artery. All three major coronary arteries contribute to the blood supply of the LV. As a result, acute myocardial ischemia resulting from a critical coronary artery stenosis or abrupt occlusion causes a predictable pattern of LV injury based on the known distribution of blood supply. In brief, the LAD and its branches (including septal perforators and diagonals) supply the medial half of the LV anterior wall, the apex, and the anterior two thirds of the interventricular septum. The LCCA and its obtuse marginal branches supply the anterior and posterior aspects of the lateral wall, whereas the RCA and its distal branches supply the medial portions of the posterior wall and the posterior one third of the interventricular septum. The coronary artery that supplies blood to the posterior descending coronary artery (PDA) defines the right or left “dominance” of the coronary circulation. Right dominance (PDA supplied by the RCA) is observed in approximately 80% of patients, whereas left dominance (PDA supplied by the LCCA) occurs in the remainder. Anastomoses between the distal regions of the coronary arteries or collateral blood vessels between the major coronary arteries also may exist that provide an alternative route of blood flow to myocardium distal to a severe coronary artery stenosis or complete occlusion. Either the RCA (approximately two thirds of patients) or the LCCA provides the sole blood supply to the posteromedial papillary muscle, which renders this crucial structure particularly vulnerable to acute ischemia or infarction. However, one third of patients may have a dual blood supply (RCA and LCCA) to the posterior papillary muscle.¹⁸ Both the LAD and the LCCA usually provide coronary blood flow to the anterolateral papillary muscle, and as a result, ischemic dysfunction of this papillary muscle is relatively uncommon.

In contrast with the LV, coronary blood flow to the RA, LA, and RV occurs throughout the cardiac cycle because both systolic and diastolic aortic blood pressures are greater than the pressure within these chambers. The RCA and its branches supply the majority of the RV, but the RV anterior wall also may receive blood from branches of the LAD. As a result, RV dysfunction may occur because of RCA or LAD ischemia. Coronary arterial blood supply to the LA is derived from branches of the LCCA.^19,20 Thus, augmented LA contractile function usually occurs in the presence of acute myocardial ischemia or infarction resulting from LAD occlusion,²¹ but such a compensatory response may not be observed during compromise of LCCA blood flow concomitant with LA ischemia.²² Branches of the RCA and the LCCA provide coronary blood flow to the RA.¹⁹ For example, a nodal artery from the RCA (55% of patients) or the LCCA (45%) supplies blood to the sinoatrial (SA) node. Similarly, the RCA or, less commonly, the LCCA branches supply blood flow to the AV node concomitant with the right or left dominance of the coronary circulation. As a result, a critical stenosis or acute occlusion in either of these two perfusion territories may adversely affect the proximal conduction system of the heart and produce hemodynamically significant bradyarrhythmias.

Conduction

The mechanism by which the heart is electrically activated plays a crucial role in its mechanical performance.²³ The SA node is the primary cardiac pacemaker in the absence of marked decreases in firing rate, conduction delays or blockade, or accelerated firing of secondary pacemakers (e.g., AV node, bundle of His). The anterior, middle (Wenckebach), and posterior (Thorel) internodal pathways transmit the initial SA node depolarization rapidly through the RA myocardium to the AV node (Table 5-1). A branch (Bachmann’s bundle) of the anterior internodal pathway also transmits the SA node depolarization from the RA to the LA across the atrial septum. The internodal pathways may be demonstrated in the electrophysiology laboratory, but microscopic examination of tissue histology usually fails to differentiate anatomically discernible bundles of morphologically distinct cardiac cells capable of more rapid impulse conduction than the atrial myocardium itself. The cartilaginous skeleton of the heart isolates the atria from the ventricles by acting as an electrical insulator. Thus, atrial depolarization is not indiscriminately transmitted throughout the heart, but instead is directed solely to the ventricles through the AV node and its distal conduction pathway, the bundle of His. This electrical isolation between the atrial and ventricular chambers and the temporal transmission delay occurring within the slowly conducting AV node establishes the normal sequential pattern of atrial followed by ventricular contraction. Abnormal accessory pathways (e.g., bundle of Kent) between the atria and ventricles may bypass the AV node and contribute to the development of reentrant supraventricular tachyarrhythmias (e.g., Wolff–Parkinson–White syndrome). The bundle of His pierces the connective tissue insulator of the cartilaginous cardiac skeleton and transmits the AV depolarization signal through the right and left bundle branches to the RV and LV myocardium, respectively, via an extensive Purkinje network located within the inner third of the ventricular walls. The bundle of His, the bundle branches, and the Purkinje network are composed of His-Purkinje fibers that assure rapid, coordinated distribution of depolarization throughout the RV and LV myocardium. This ingenious electrical design allows synchronous ventricular contraction and efficient, coordinated ejection. In contrast, artificial cardiac pacing that bypasses the normal conduction system (e.g., epicardial RV pacing) produces dyssynchronous LV activation, causes a contraction pattern that may result in suboptimal LV systolic function, and is a frequent cause of a new regional wall motion abnormality after cardiopulmonary bypass in cardiac surgical patients. This form of contractile dyssynchrony is also associated with chronic RV apical pacing (e.g., used for the treatment of sick-sinus syndrome or an AV conduction disorder) and is known to cause detrimental effects on LV chamber geometry and function.²⁴ Furthermore, recognition of the crucial relation between a normal electrical activation sequence and LV contractile synchrony forms the basis for the successful use of cardiac resynchronization therapy in some patients with congestive HF.²⁵

TABLE 5-1 Cardiac Electrical Activation Sequence

Katz AM: Physiology of the Heart, 3rd ed. Lippincott Williams and Wilkins, 2001.

Ultrastructure

The ultrastructure of the cardiac myocyte is a remarkably elegant example of the architectural principle “form follows function.” The external membrane of the cardiac muscle cell is known as the sarcolemma. This bilayer lipid membrane contains ion channels (e.g., Na⁺, K⁺, Ca²⁺, Cl⁻), active and passive ion transporters (e.g., Na⁺-K⁺ ATPase, Ca²⁺-ATPase, Na⁺-Ca²⁺ or -H⁺ exchangers), receptors (e.g., β₁-adrenergic, muscarinic cholinergic, adenosine, opioid), and transport enzymes (e.g., glucose transporter) that modulate intracellular ion concentrations, regulate homeostasis of electrophysiology, mediate signal transduction, and provide substrates for metabolism. Deep sarcolemmal invaginations, termed transverse (“T”) tubules, penetrate the myoplasm and facilitate rapid, synchronous transmission of cellular depolarization (Figure 5-3). The myocyte contains very large numbers of mitochondria responsible for the generation of high-energy phosphates (e.g., adenosine triphosphate [ATP], creatine phosphate) required for contraction and relaxation. The sarcomere is the contractile unit of cardiac myocyte and contains myofilaments arranged in parallel cross-striated bundles of thin (containing actin, tropomyosin, and the troponin complex) and thick (primarily composed of myosin and its supporting proteins) fibers. Sarcomeres are connected in series, and as a result, the long and short axes of each myocyte simultaneously shorten and thicken, respectively, during contraction. Light and electron microscopic observations form the basis for the description of sarcomere structure. Thick and thin fibers functionally interact in an area known as the “A” band that becomes wider (indicating more pronounced overlap) as the sarcomere shortens. The sarcomere region containing thin filaments alone is termed the “I” band; the width of this band is reduced during myocyte contraction. A “Z” (derived from the German zuckung, meaning “twitch”) line bisects each “I” band. The “Z” line denotes the border at which two adjacent sarcomeres are joined. Thus, an “A” band and two half “I” bands (between the “Z” lines) describe the length of each sarcomere. The “A” band also contains a central “M” band composed of thick filaments oriented in a cross-sectional hexagonal arrangement by myosin binding protein C.

Figure 5-3 Arnold Katz’s schematic illustration depicting the ultrastructure of the cardiac myocyte.

Katz AM: Physiology of the Heart, 3rd ed. Lippincott Williams and Wilkins, 2001.

Each cardiac myocyte contains a highly intertwined sarcoplasmic reticulum (SR) network that surrounds the contractile protein bundles. The SR serves as the primary calcium (Ca²⁺) reservoir of the cardiac myocyte, and its extensive distribution assures almost homogenous dispersal and subsequent reaccumulation of activator Ca²⁺ throughout the myofilaments during contraction and relaxation, respectively. The SR contains specialized structures, known as subsarcolemmal cisternae, located adjacent to the sarcolemma and T tubules. These subsarcolemmal cisternae contain a dense concentration of ryanodine receptors that function as the SR’s primary Ca²⁺ release channel and facilitate Ca²⁺-induced Ca²⁺ release immediately on sarcolemmal depolarization. The contractile apparatus and the mitochondria that supply its energy comprise more than 80% of the myocyte’s total volume, whereas the cytosol and nucleus occupy less than 15%. This observation emphasizes that contraction, and not de novo protein synthesis, is the predominant function of the cardiac myocyte. Intercalated disks not only mechanically join adjacent myocytes via the fascia adherens (which links actin molecules at each Z line) and desmosomes, but also create electrical transparency between myocytes through gap junctions that allow diffusion of ions and small molecules.

Proteins of the Contractile Apparatus

The contractile apparatus is composed of six major components: myosin, actin, tropomyosin, and the three-protein troponin complex. Myosin (molecular weight = 500 kDa; length = 0.17 μm) contains a pair of intertwined α-helical proteins (tails), each with a globular head that binds the actin molecule, and two adjoining pairs of light chains. Enzymatic digestion of myosin reveals the presence of “light” (composed of the tail sections) and “heavy” (containing the globular heads and the light chains) meromyosin. The primary structural support of the myosin molecule is the elongated tail section (“light” meromyosin). The globular heads of the myosin dimer contain two “hinges” that are located at the distal light chain tail-double helix junction. These hinges are responsible for myofilament shortening during contraction. The binding of the myosin head to the actin molecule stimulates a cascade of events initiated by activation of a myosin ATPase that mediates both hinge rotation and actin release during contraction and relaxation, respectively. The activity of this actin-activated myosin ATPase is a major determinant of the maximum velocity of sarcomere shortening. Of note, several different myosin ATPase isoforms have been identified in adult and neonatal atrial and ventricular myocardium that are distinguished by their relative ATPase activity. Myosin molecules are oriented in series along the length of the thick filament and are joined “tail to tail” in the filament’s center at the M line. Such an orientation produces equivalent shortening of each half of the sarcomere as the actin molecules are pulled toward the center.

The four light chains in the myosin complex are considered “regulatory” or “essential.” Regulatory myosin light chains affect the interaction between myosin and actin by modulating the phosphorylation state of Ca²⁺-dependent protein kinases. In contrast, essential light chains serve vital, but currently undefined, roles in myosin activity because their removal denatures the myosin molecule. Notably, LV hypertrophy is characterized by myosin light chain isoform alterations from ventricular to atrial forms that may play an important role in the contractile dysfunction associated with this disorder.²⁶ These interesting data suggest that genetic modulation of light-chain isoform expression may form the basis for pathologic changes in function in some cardiac disease states. Thick filaments are not only composed of myosin and its binding protein, but also contain titin, a long elastic molecule that attaches myosin to the Z lines. Titin is an important contributor to myocardial elasticity and, similar to a bidirectional spring, acts as a “length sensor” by establishing greater passive restoring forces as sarcomere length approaches its maximum or minimum.²⁷ Titin compression and stretching are observed during decreases and increases in load that serve to limit additional shortening and lengthening of the sarcomere, respectively. Thus, titin is another important elastic element (in addition to actin and myosin) that mediates the stress-strain biomechanical properties of cardiac muscle.²⁸

Actin is the major component of the thin filament and is composed of a 42-kDa oval-shaped, globular protein (known as the “G” form; diameter = 5.5 nm). Actin exists in a polymerized filamentous configuration (“F” form) wound in double-stranded helical chains of G-actin monomers that resemble two intertwined strands of pearls. Each complete helical revolution of F-actin contains 14 G-actin monomers and is 77 nm in length. F-actin does not directly hydrolyze high-energy nucleotides (e.g., ATP), but the molecule does bind adenosine diphosphate (ADP) and divalent cations such as Ca²⁺ and Mg²⁺. Actin functions as the “activator” (hence its name) of myosin ATPase through its reversible binding with myosin. This actin-myosin complex is capable of hydrolyzing ATP, thereby supplying the energy required to cause the conformational changes in the myosin heads that mediate the cycle of contraction and relaxation within the sarcomere. Tropomyosin (weight = 68 and 72 kDa; length = 40 nm) is a major inhibitor of the interaction between actin and myosin, and consists of a rigid double-stranded α-helix protein linked by a single disulfide bond. Human tropomyosin contains both α and β isoforms (34 and 36 kDa, respectively), and may exist as either a homodimer or heterodimer.²⁹ The Ca²⁺-dependent interaction of tropomyosin with the troponin complex is the primary mechanism by which excitation-contraction coupling occurs; that is, the association between sarcolemmal membrane depolarization and the resultant binding of actin and myosin that is responsible for contraction of the cardiac myocyte. Tropomyosin also stiffens the thin filament through its position within the longitudinal cleft between the interwoven F-actin helices. Several cytoskeletal proteins (e.g., α- and β-actinin, nebulette) anchor the thin filaments to the Z lines of the sarcomere.³⁰

The troponin complex consists of three proteins that are critical regulators of the contractile apparatus. Each troponin protein serves a distinct role.³¹ Troponin complexes are interspersed at 40-nm intervals along the thin filament. A highly conserved, single isoform of troponin C (named for the molecule’s Ca²⁺ binding ability) exists in cardiac muscle. The structure of this protein consists of a central nine-turn α helix separating two globular regions that contain four discrete divalent cation-binding amino acid sequences, two of which (termed “sites I and II”) are Ca²⁺ specific. As a result, the troponin C molecule is able to directly respond to the acute changes in intracellular Ca²⁺ concentration that accompany contraction and relaxation. Troponin I (“I” for “inhibitor”; 23 kDa) exists in a single isoform in cardiac muscle. Troponin I alone weakly interferes with actin-myosin interaction, but becomes the major inhibitor of actin-myosin binding when combined with tropomyosin. This inhibition is responsive to receptor-operated signal transduction, as the troponin I molecule contains a serine residue that is susceptible to protein kinase A (PKA)–mediated phosphorylation through the intracellular second messenger cyclic adenosine monophosphate. Such phosphorylation of this serine residue reduces the ability of troponin C to bind Ca²⁺, an action that facilitates relaxation during administration of positive inotropic drugs including β-adrenoceptor agonists (e.g., dobutamine) and phosphodiesterase fraction III (PDE III) inhibitors (e.g., milrinone). Troponin T (the “T” identifies the protein’s ability to bind other troponin molecules and tropomyosin) is the largest of the troponin proteins and has four major human isoforms. Troponin T serves as an anchor for the other troponin molecules and also may influence the relative Ca²⁺ sensitivity of the troponin C.³²

Ca²⁺-Myofilament Interaction

Ca²⁺-troponin C binding produces a sequence of conformational changes in the troponin-tropomyosin complex that expose the specific myosin-binding site on actin (Figure 5-4). Small amounts of Ca²⁺ are bound to troponin C when intracellular Ca²⁺ concentration is low during diastole (10⁻⁷ M). Under these conditions, the troponin complex confines each tropomyosin molecule to the outer region of the groove between F-actin filaments, thereby effectively preventing the interaction of myosin and actin by blocking the formation of cross-bridges between these proteins. This resting inhibitory state is rapidly transformed by the 100-fold increase in intracellular Ca²⁺ concentration (to 10⁻⁵ M) occurring as a consequence of sarcolemmal depolarization that opens L- and T-type Ca²⁺ channels, allows Ca²⁺ influx from the extracellular space, and stimulates ryanodine receptor–mediated, Ca²⁺-induced Ca²⁺ release from the SR. Ca²⁺-troponin C binding occurs under these conditions, and this action not only elongates the troponin C protein but enhances its interactions with troponin T and I. Such Ca²⁺-mediated allosteric alterations in the structure of the troponin complex weaken the interaction between troponin I and actin, promote repositioning of the tropomyosin molecule relative to the F-actin filaments, and minimize the previously described inhibition of actin-myosin binding by tropomyosin that is observed during low intracellular Ca²⁺ concentrations.³³ Thus, Ca²⁺-troponin C binding stimulates a sequence of alterations in the chemical conformation of the regulatory proteins that reveal the binding site for myosin on the actin molecule and allow cross-bridge formation and contraction to occur. Subsequent dissociation of Ca²⁺ from troponin C fully reverses this antagonism of inhibition, prevents further myosin-actin interaction, and facilitates relaxation by rapidly restoring of the original conformation of the troponin-tropomyosin complex on F-actin.

Figure 5-4 Cross-sectional schematic illustration demonstrates the structural relationship between the troponin-tropomyosin complex and the actin filament under resting conditions (diastole; left) and after Ca²⁺ binding (systole; right). Ca²⁺ binding produces a conformational shift in the troponin-tropomyosin complex toward the groove between the actin molecules, thereby exposing the myosin binding site on actin. TnC, troponin C; TnI, troponin I; TnT, troponin T.

Katz AM: Physiology of the Heart, 3rd ed. Lippincott Williams and Wilkins, 2001.

An energy-dependent ion pump (Ca²⁺-ATPase) located in the SR membrane (abbreviated as “SERCA” for SR Ca²⁺-ATPase) removes most Ca²⁺ ions from the myofilaments and the myoplasm after the sarcolemmal membrane is repolarized. This activator Ca²⁺ is stored in the SR at a concentration of approximately 10⁻³ M and is transiently bound to calsequestrin and calrectulin until the next sarcolemmal depolarization occurs and ryanodine receptor–activated SR channels open again. Another Ca²⁺-ATPase and a Na⁺/Ca²⁺ exchanger passively driven by ion concentration gradients, each located in the sarcolemmal membrane, also play roles in the removal of substantially smaller amounts of Ca²⁺ from the myoplasm after repolarization. Phospholamban is a small protein (6 kDa) located in the SR membrane that modulates the activity of SERCA by partially inhibiting the dominant form (type 2a) of this main Ca²⁺ pump under baseline conditions. However, PKA-induced phosphorylation of phospholamban antagonizes this baseline inhibition and enhances SERCA-mediated Ca²⁺ uptake into the SR.³⁴ Thus, drugs such as dobutamine and milrinone that act by modifying PKA-mediated signal transduction enhance the rate and extent of relaxation by facilitating Ca²⁺ reuptake (positive lusitropic effect), while simultaneously increasing the amount of Ca²⁺ available for the next contractile activation (positive inotropic effect).

Biochemistry of Myosin-Actin Interaction

A four-component kinetic model is most often used to describe the biochemistry of cardiac muscle contraction (Figure 5-5).³⁵ High-affinity binding of ATP to the catalytic domain of myosin initiates a coordinated sequence of events that results in sarcomere shortening. The myosin ATPase enzyme hydrolyzes the ATP molecule into ADP and inorganic phosphate. These products remain bound to myosin, thereby forming an “active” complex that retains the reaction’s chemical energy as potential energy. In the absence of actin, ADP and phosphate eventually dissociate from myosin and the muscle remains relaxed. The activity of myosin ATPase is substantially enhanced when the myosin-ADP-phosphate complex is bound to actin, and under these conditions, the energy released by ATP hydrolysis is translated into mechanical work. Myosin binding to actin releases the phosphate anion from the myosin head, thereby producing a tension-inducing molecular conformation within the cross-bridge.³⁶ Release of ADP and potential energy from this “activated” orientation combine to rotate the cross-bridge (“power stroke”) at the hinge point separating the helical tail from the globular head of the myosin molecule. Each cross-bridge rotation generates approximately 3.5 × 10⁻¹² newtons of force, and myosin moves 11 nm along the actin molecule.³⁷ The myosin-active complex does not immediately dissociate after rotation of the myosin head rotation and ADP release, but instead remains in a low-energy bound (“rigor”) state. Subsequent dissociation of the myosin and actin molecules occurs only when a new ATP molecule binds to myosin. This four-step process is then repeated, assuming an adequate ATP supply and lack of inhibition of the myosin-binding site on actin by the troponin-tropomyosin complex.

Figure 5-5

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