188 23 Structure and Function of the Heart LUCIANA RODRIGUEZ GUERINEAU, JAYANI ABEYSEKERA, V BEN SIVARAJAN, AND STEVEN M SCHWARTZ • The basic form of the human heart and great vessels is complete 8 we[.]
23 Structure and Function of the Heart LUCIANA RODRIGUEZ GUERINEAU, JAYANI ABEYSEKERA, V BEN SIVARAJAN, AND STEVEN M SCHWARTZ Anatomic Development and Structure Segmental Anatomy The normal heart can be divided into three major segments—the atria, ventricles, and arterial trunks—which are connected through atrioventricular (AV) and ventriculoarterial valves, respectively Each segment has defining components that differentiate the right- and left-sided structures The atria have five structural components: (1) the venous return (typically, inferior vena cava, superior vena cava, and coronary sinus to the right atrium and pulmonary veins to the left); (2) the appendage and its extent of pectinate muscles (the constant feature of a right vs left atrium); (3) the septum; (4) the body; and (5) the vestibule continuing with the AV valve The normal orientation of the ventricles with respect to each other can be described as D-looped or with right-hand topology depending on the nomenclature system that is used, and have three components: the inlet portion, the trabecular zone, and the outlet In terms of the AV valves, the tricuspid valve (with septophilic attachments and discontinuity with the semilunar valve) is always associated with the morphologic right ventricle and the mitral valve (septophobic) with the morphologic left ventricle In a structurally normal heart, the ventriculoarterial valves will connect the pulmonary artery to the right ventricle through the leftward and anterior pulmonary valve and the aorta to the left ventricle through the posterior rightward aortic valve The identification of each segment and connections is the basis of the segmental approach in classification of congenital heart diseases.1 188 • • The basic form of the human heart and great vessels is complete weeks after conception, after which the structures grow and mature Immediately after birth, there is a large increase in total body oxygen consumption and cardiac output to approximately twice its values later in life The determinants of cardiac output—heart rate, loading conditions (preload and afterload), and contractility—influence each other as demonstrated by the Frank-Starling mechanism, force-frequency relationship, end-systolic pressure-volume relationship, and preload reserve • • • • PEARLS Although large arteries are regarded as conduits and capillaries as vessels allowing transport of substances to and from the tissues, many substances can move across arterial walls Standard echocardiographic assessments (ejection and shortening fraction) reflect myocardial performance (loaddependent measures) as opposed to true contractility Assessments of adequacy of ventricular-vascular coupling (adequacy of contractile status with a given preload given the afterload conditions) can be assessed by noninvasive or invasive methods Abnormalities in cardiac segmentation are often accompanied by ipsilateral changes in respiratory and gastrointestinal organ sidedness (i.e., isomerism) The conduction system is formed by superspecialized myocardium that has an enhanced ability to generate and disseminate the cardiac impulse The normal electrical impulse originates in the sinus node (high right atrium); disseminates through the atrial myocardium; reaches the AV node, where it is delayed; and then rapidly spreads through the bundle of His to bifurcate in its right and left branches and activate the ventricular myocardium The delay in the AV node gives time for the atrium to contract before initiating ventricular contraction The AV node is normally the only electrical connection between the atria and ventricles, as the fibrofatty tissues of the AV grooves provide electrical insulation between atrial and ventricular masses The right and left coronary artery systems provide arterial supply to the myocardium They emerge from the aorta at two of the three respective coronary sinuses The left coronary artery typically divides into the circumflex and anterior descending branches The circumflex provides arterial blood supply to the lateral and posterior wall of the left ventricle and left anterior descending branch to the anterior wall of the left ventricle and anterior part of the interventricular septum The right coronary artery supplies the right ventricular (RV) free wall and inferior part of the interventricular septum, where it gives rise to the posterior descending artery (90% of the population, termed right coronary arterial dominance) The venous return from the heart is collected into the major veins, which drain in the coronary sinus Minor cardiac veins from the anterior surface of the right ventricle drain directly CHAPTER 23 Structure and Function of the Heart into the RV cavity in the same way that small veins from the atrial walls (the Thebesian veins) open directly into the respective atria.2 Innervation of the Heart The heart has sympathetic and parasympathetic innervations that are tonically active and responsible for physiologic changes in heart rate Adrenergic (sympathetic), muscarinic (parasympathetic), and other receptors appear early and are functional even before innervation Parasympathetic innervation precedes sympathetic innervation in all species.3–5 Innervation is present in the earliest viable human premature infants but may not be fully mature Cardiac sympathetic nerve fibers arise from cervical sympathetic and stellate ganglia Vagal nerve fibers descending from medullary centers supply both atria and ventricles and the proximal portion of the bundle of His The distal part of the bundle of His has only sympathetic nerve supply Sympathetic and vagal afferents leaving the heart carry information from baroreceptors that respond to high pressures in the ventricles and to lower pressures in the atria, cavae, and pulmonary veins as well as from chemoreceptors that respond to locally produced substances, such as bradykinin and prostaglandin.6 Ductus Arteriosus The ductus arteriosus forms from the embryonic left sixth aortic arch and joins the main pulmonary artery The ductus is kept open by a balance between prostaglandin E2 (PGE2) and endothelin-1 (ET-1), both of which are formed in its wall and circulate from other sites Initially, the ductus is sensitive to the dilating action of PGE2 However, later in gestation, it becomes less sensitive to dilator and more sensitive to constrictor prostaglandins.7–9 After birth, oxygen reacts with a cytochrome P-450 and causes release of ET-1 (the most powerful ductus constrictor).10 A switch from dilator to constrictor prostaglandins occurs In addition, oxygen modulates the function of mitochondrial electron chain transport, causing a net influx of calcium and, ultimately, ductal constriction.11–13 These constrictor effects overpower the dilating effect of nitric oxide, which is released from the ductus when oxygen tension rises.14 The ductus constricts, usually within the first 24 hours and almost invariably within weeks The lumen then becomes permanently occluded by fibrosis.9,15 189 afterload on mural thickness The ventricular septum is flattened in the fetus After birth, it bulges into the right ventricle and functions like part of the left ventricle Muscle fibers in the ventricles form a complex helical array Fibers in the left ventricular (LV) midwall are circumferential, parallel to the AV groove From this position, the fibers twist gradually as they move toward each surface so that at the epicardial surface they are 75 degrees and at the endocardial surface 60 degrees from the circumferential fibers (analogous to the motion of wringing of a towel).17 This disposition of fibers is the basis of the twist or torsional LV deformation during systole Some investigators believe that the muscle fiber layers form one continuous sheet that is wrapped around itself like a turban.18 When the ventricle is dilated, the fiber angles change and become less effective in ejecting blood.19 Microscopic Anatomy The heart wall is made of a thick myocardium consisting of muscle fibers intermingled by fibroblasts that contribute to the formation of the extracellular matrix, the internal endocardium, which creates a nonthrombotic surface and external epicardium covering the heart The myocardium works as a syncytium made of branching fibers, each consisting of bundles of myocytes in series The myocytes are joined to adjacent myocytes by a specialized junction: the intercalated disc that provides mechanical connection by the adherens junctions (desmosomes and other membrane proteins) and electrical connection by the gap junction (connexins and N-cadherin).20–22 Cardiomyocyte Cardiomyocytes are specialized cardiac cells that can be divided in two cell types: those forming the conduction system and those performing the contractile work The major components of the myocyte are the sarcomeres, which contain the myofibrillar contractile apparatus; the mitochondria, which house enzymes for energy production; the sarcoplasmic reticulum; and the cytosol The sarcolemma is the cell membrane, which has extensions into the cytoplasm The numerous proteins in these structures not only play a role in normal function but, if abnormal for genetic or extraneous reasons, contribute to myocardial dysfunction.23 Development of the Human Heart Contractile Apparatus The basic form of the human heart and great vessels is complete weeks after conception, after which the structures grow and mature In the embryo, coronary arteries form from an aortic peritruncal plexus and join the aorta to supply flow to the thickening heart muscle, which can no longer get enough blood from sinusoids from the ventricular cavity The ventricular mass enlarges by cellular hyperplasia (cell division) and hypertrophy (cell enlargement) Hyperplasia is the major mechanism for which ventricular mass increases in the fetal heart, transitioning to hypertrophy as the dominant mechanism in postnatal life.16 Ventricular growth is believed to depend on flow, as conditions that divert flow from a ventricle are usually associated with hypoplasia of that ventricle and its associated great artery Before birth, the left and right ventricles have equal wall thickness After birth and clamping of the umbilical cord, there is a rise in systemic vascular resistance and a decrease in pulmonary vascular resistance As a result, the left ventricle becomes thicker than the right ventricle, highlighting the impact of workload and The cardiomyocytes are filled with aligned contractile myofibrils Each myofibril is composed of thin (mainly actin) and thick (myosin) filaments organized into contractile functional units called sarcomeres The sarcomere is defined as the structure between two transverse Z lines.24–26 On each side of the Z line is a light zone, the I (isotropic) band, and in the center of the sarcomere are two dark zones, the A (anisotropic) bands, separated by a light H band in the middle of which is a dark, thin M band The I bands contain paired thin filaments of actin coiled in a helix and attached to the Z lines Two long tropomyosin filaments lie in the grooves between each pair of actin filaments (Fig 23.1).27 Every 400 Å, near the crossover points of two actin filaments, is a troponin complex with the following three distinct troponins: (1) troponin T, which binds troponin to tropomyosin; (2) troponin I, which inhibits actin-myosin interaction; and (3) troponin C, which is a high-affinity calcium receptor The thin actin filaments overlap with thick myosin filaments at the A bands These myosin filaments are composed of light and heavy chains The 190 S E C T I O N I V Pediatric Critical Care: Cardiovascular Strain Plasma membrane Integrin Ca2+ Troponin T Troponin C Troponin I Actin Thin filament α-Tropomyosin Myosin-binding β-Myosin protein C heavy chain Thick filament PEVK region Calsarcin T-cap Calcineurin Titin MLP cGMP PKG PDE5 α-Actinin Z-disk • Fig 23.1 Integration of myofibril contraction (actin-myosin complex formation) to attachments to the Z lines and cytoskeleton via various ultrastructural proteins Ca21, Calcium ion; cGMP, cyclic guanosine monophosphate; MLP, muscle LIM protein; PDE5, phosphodiesterase 5; PKG, protein kinase G; T-cap, titin cap (Modified from Mudd JO, Kass DA Tackling heart failure in the twenty-first century Nature 2008;451:919–928.) light chains coil around each other to form the long core of the myosin molecule The heavy chains form globular myosin heads that project from the sides of the thick filament toward the actin molecules (see Fig 23.1) A collar of cardiac myosin-binding protein C encircles the thick filaments Mutations of this protein are a common cause of hypertrophic cardiomyopathy.28 Between two A bands, there is usually a thin, lighter band, the H band, which has myosin but no actin filaments.26,27 Titin is a giant protein and is the third most abundant fibrillar protein It extends from the Z band to the M band, has two isoforms, and is the main protein responsible for the elastic behavior of the myocyte.29 It is essential for sarcomere assembly and for sensing sarcomere length since it is speculated to be the major regulator of thick filament length30,31 and, with myomesin (not shown in Fig 23.1), supports the actomyosin filaments (see Fig 23.1) Titin mutations, at present, are one of the most common etiologies of inherited dilated cardiomyopathy.32,33 Sarcolemma and Sarcoplasmic Reticulum The cell membrane contains receptors, ion channels, pumps, and exchangers It has indentations overlying the Z bands; from these indentations, small tubules termed T tubules (for transverse) penetrate the cell Abutting against the T tubules are dilated expansions of the sarcoplasmic reticulum (junctional reticulum or cisternae), which join the free sarcoplasmic reticulum, a network of longitudinal tubules inside the cell that surround the thick (myosin) filaments These tubular systems modulate the entry of calcium to, or its exclusion from, the cytoplasm.3,24 The cisternae contain the calcium-binding protein calsequestrin, whereas the longitudinal tubules contain phospholamban and the adenosine triphosphate (ATP)-dependent calcium pump.3,34 Phospholamban inhibits the affinity of the sarcoplasmic reticulum Ca21-adenosine triphosphatase (SERCA) pump for calcium, and phospholamban phosphorylation relieves the inhibition and increases calcium entry, with a resulting increase in inotropy.35–38 In heart failure, phospholamban phosphorylation is decreased,39 leading to decreased SERCA activity.40,41 A similar decrease in SERCA has been found in sepsis42 and in some forms of dilated cardiomyopathy.43 Cisternae store and release activator calcium, whereas longitudinal tubules remove calcium from the cytosol Calcium release is primarily via the calcium-activated calcium release channel termed the ryanodine receptor Mutations in the ryanodine receptor and calsequestrin genes are implicated in catecholaminergic polymorphic ventricular tachycardia.44 Both T tubules and sarcoplasmic reticulum are sparse, undifferentiated, and disorganized early in gestation but increase and differentiate markedly late in gestation and after birth in mammals Therefore, the immature heart depends mainly on extracellular sources for activator calcium,3,27 partly explaining its marked calcium sensitivity 191 CHAPTER 23 Structure and Function of the Heart Cytoplasm During development, the proportion of mitochondria in the myocyte increases, particularly at the time of birth, and mitochondria become larger and develop more complex cristae.3 In the adult, approximately 30% to 40% of the muscle mass is made up of mitochondria The cytosol contains other calcium-binding proteins3,45 and other major proteins, such as tubulin and desmin adhesion proteins, stimulated by growth factors from the myocyte, are present in greatest amount in the neonate, decrease with postnatal age, and increase again during hypertrophy.62,63 Other elements in the extracellular matrix (e.g., laminin, fibronectin, and tenascin) play a major role during morphogenesis and during contraction64 and are important mediators in hypertrophy Cytoskeleton and Extracellular Matrix For contractile proteins to shorten the entire myocyte, they must be linked to both the cell membrane and extracellular matrix Longitudinal connections are made via the Z lines, representing disks that contain proteins such as a-actinin and filamin, which connect the actin and titin filaments of adjacent myocytes.46,47 More lateral connections are made by the extrasarcomeric skeleton There is an intermyofibrillar cytoskeleton with intermediate filaments, microfilaments, and microtubules.46,48–50 Desmin intermediate filaments provide a three-dimensional scaffold throughout the extrasarcomeric cytoskeleton and connect longitudinally to adjacent Z disks and laterally to subsarcolemmal costameres.48,50 Costameres are subsarcolemmal domains that contain different adhesion complexes connecting the cytoskeletal actin filaments with transmembrane proteins.51–53 These proteins help to fix sarcomeres to the lateral sarcolemma, stabilize the T-tubular system, and connect the sarcolemma to the extracellular matrix In many of the genetic dilated cardiomyopathies, these proteins are abnormal,54–56 which impacts muscle function Extracellular collagen plays a major role in cell-cell and cellvessel interactions and in ventricular stiffness.57–60 The relationship between sarcomeres and cytoskeleton changes with maturation, perhaps accounting for maturational differences in the resting sarcomere’s mean length in myocytes.61 Additionally, cell Physiologic Development and Function Myocardial Mechanics: Cardiac Sarcomere Function Excitation-Contraction Coupling As the electrical impulse propagates through the cardiac muscle, myocyte membranes depolarize Extracellular calcium at the sarcolemmal membrane and T tubules enters the intracellular space rapidly Spread of electrical excitation into the myocyte via the T tubules also causes release of intracellular calcium from the sarcoplasmic reticulum.24,65,66 Cytosolic calcium increases from a concentration of 1027 M in diastole to 1025 M in systole When calcium then binds to troponin C, the inhibitory effect of troponin I is antagonized, and a conformational change of troponin and tropomyosin exposes the actin-myosin binding sites.24,27,65,66 These sites interact with the myosin heads to form cross-bridges (Fig 23.2) The myosin heads rotate, generate force, and move the actin filaments, just as oars move a boat through the water Interaction between actin and myosin pulls the two Z lines toward each other, generating force and shortening the muscle Increasing intracellular calcium results in greater cross-bridge formation and a greater generated force Isoforms of the troponins and tropomyosin change during devel- Calcium Influx and Phosphorylation Ca2+ Contraction Cycle Calmodulin Ca2+ ADP Pi Channel Myosin kinase IP3 Phospholipase C ADP ATP Pi Myosin Pi ADP Myosin phosphatase (dephosphorylation) Pi Binds actin Ca-calmodulin SR Receptor Latch State Pi Pi ADP Myosin phosphatase ADP Pi P ATP ATP Pi • Fig 23.2 Cardiomyocyte Pi calcium cycling and adenosine-triphosphate (ATP) utilization during actinmyosin complex formation ADP, Adenosine diphosphate; Ca21, calcium ion; Pi, phosphate ion "Latch state" 192 S E C T I O N I V Pediatric Critical Care: Cardiovascular opment, but the functional effects of these changes are unknown.3,67 Troponin I is less sensitive to a fall in pH in the fetus than in the adult, which could be protective in perinatal acidosis The myosin head contains an adenosine triphosphatase (ATPase) that liberates energy from ATP The activity of the ATPase determines the velocity of shortening of unloaded muscle by affecting the rate of attachment and detachment of the crossbridges.3,68 the muscle must work against after contraction has been initiated, or afterload, is created using weights added to the lever after initial length is set Stretching relaxed muscle produces an exponentiallike increase in passive tension (Fig 23.3B) This elasticity results mainly from titin.29,69–71 At very low sarcomere lengths, the actin filaments from each Z line overlap each other (1.6 and 1.8 mm in Fig 23.3C) As the sarcomere lengthens, the Z lines move farther apart, and a gap appears between the two sets of actin filaments (2.5 mm in Fig 23.3C) When the sarcomere reaches a length of approximately 2.2 mm, there is a maximal overlap between actin and myosin filaments26,66,68 (2.2 mm in Fig 23.3C) At longer muscle and sarcomere lengths, actin and myosin filaments overlap less The maximal sarcomere length is 3.0 mm Further elongation of the muscle occurs by slippage of fibers and not by further sarcomere lengthening.26,66,68 Sarcomere Length-Tension Relationships Sarcomere length-tension relationships have been investigated using isolated cardiac muscle strips Most commonly, a papillary muscle is connected between a lever and a force transducer (Fig 23.3A) Loading before contraction, or preload, is adjusted using weights attached to the other end of the lever Loading that Micrometer lever stop 100 Length transducer Increased contractility Tension (percent of maximum) Lever Electrode plates Papillary muscle Oxygen supply 80 60 B Z 1.0 µm Thin filament 1.5 µm bridges 100 (Lmax) Percent of muscle length 1.0 µm Z Thick filament 3.5 µm 2.5 µm H zone A Active tension Resting tension Afterload Preload Force transducer Control 2.2 µm Optimum "overlap" 2.0 µm 1.8 µm 1.6 µm C Double overlap • Fig 23.3 (A) Isolated muscle strip in a water bath and attached to transducers for measuring force and length Preload is set by the lever stop (B) Relationship between muscle length and resting tension or active tension at three different contractile levels (C) Relationships of sarcomere length, positions of the actin and myosin filaments, and contractile force (A, From Parmley WW, Tyberg JV Determinants of myocardial oxygen consumption In: Yu PN, Goodwin JF, eds Progress in Cardiology Philadelphia: Lea & Febiger; 1976 B and C, Modified from Sonnenblick EH Myocardial ultrastructure in the normal and failing heart In: Braunwald E, ed The Myocardium: Failure and Infarction New York: HP Publishing; 1974.) ... ductus constricts, usually within the first 24 hours and almost invariably within weeks The lumen then becomes permanently occluded by fibrosis.9,15 189 afterload on mural thickness The ventricular... project from the sides of the thick filament toward the actin molecules (see Fig 23.1) A collar of cardiac myosin-binding protein C encircles the thick filaments Mutations of this protein are a common... (anisotropic) bands, separated by a light H band in the middle of which is a dark, thin M band The I bands contain paired thin filaments of actin coiled in a helix and attached to the Z lines Two long