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. 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.

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 (PGE ₂ ) 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 PGE ₂ . However, later in gestation, it becomes less sensitive to dilator and more sensitive to constrictor prostaglandins. After birth, oxygen reacts with a cytochrome P-450 and causes release of ET-1 (the most powerful ductus constrictor). 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. These constrictor effects overpower the dilating effect of nitric oxide, which is released from the ductus when oxygen tension rises. The ductus constricts, usually within the first 24 hours and almost invariably within 3 weeks. The lumen then becomes permanently occluded by fibrosis. ^,

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.

Contractile apparatus

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. 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 ). 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 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. Between two A bands, there is usually a thin, lighter band, the H band, which has myosin but no actin filaments. ^,

Integration of myofibril contraction (actin-myosin complex formation) to attachments to the Z lines and cytoskeleton via various ultrastructural proteins. Ca ²⁺ , 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.)

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. It is essential for sarcomere assembly and for sensing sarcomere length since it is speculated to be the major regulator of thick filament length ^, 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. ^,

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. ^,

The cisternae contain the calcium-binding protein calsequestrin, whereas the longitudinal tubules contain phospholamban and the adenosine triphosphate (ATP)-dependent calcium pump. ^, Phospholamban inhibits the affinity of the sarcoplasmic reticulum Ca ²⁺ -adenosine triphosphatase (SERCA) pump for calcium, and phospholamban phosphorylation relieves the inhibition and increases calcium entry, with a resulting increase in inotropy. In heart failure, phospholamban phosphorylation is decreased, leading to decreased SERCA activity. ^, A similar decrease in SERCA has been found in sepsis and in some forms of dilated cardiomyopathy. 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. 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, ^, partly explaining its marked calcium sensitivity.

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. In the adult, approximately 30% to 40% of the muscle mass is made up of mitochondria. The cytosol contains other calcium-binding proteins ^, and other major proteins, such as tubulin and desmin.

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 α-actinin and filamin, which connect the actin and titin filaments of adjacent myocytes. ^, More lateral connections are made by the extrasarcomeric skeleton. There is an intermyofibrillar cytoskeleton with intermediate filaments, microfilaments, and microtubules. ^, Desmin intermediate filaments provide a three-dimensional scaffold throughout the extrasarcomeric cytoskeleton and connect longitudinally to adjacent Z disks and laterally to subsarcolemmal costameres. ^, Costameres are subsarcolemmal domains that contain different adhesion complexes connecting the cytoskeletal actin filaments with transmembrane proteins. 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, which impacts muscle function.

Extracellular collagen plays a major role in cell-cell and cell-vessel interactions and in ventricular stiffness. The relationship between sarcomeres and cytoskeleton changes with maturation, perhaps accounting for maturational differences in the resting sarcomere’s mean length in myocytes. Additionally, cell 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. ^, Other elements in the extracellular matrix (e.g., laminin, fibronectin, and tenascin) play a major role during morphogenesis and during contraction and are important mediators in hypertrophy.

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. ^{, ,}

Cytosolic calcium increases from a concentration of 10 ⁻⁷ M in diastole to 10 ⁻⁵ 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. ^{, , ,} 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 development, but the functional effects of these changes are unknown. ^, Troponin I is less sensitive to a fall in pH in the fetus than in the adult, which could be protective in perinatal acidosis.

Cardiomyocyte calcium cycling and adenosine-triphosphate (ATP) utilization during actin-myosin complex formation. ADP, Adenosine diphosphate; Ca ²⁺ , calcium ion; P _i , phosphate ion.

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 cross-bridges. ^,

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. 23.3 A). Loading before contraction, or preload , is adjusted using weights attached to the other end of the lever. Loading that 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 exponential-like increase in passive tension ( Fig. 23.3 B). This elasticity results mainly from titin. ^, At very low sarcomere lengths, the actin filaments from each Z line overlap each other (1.6 and 1.8 μm in Fig. 23.3 C). As the sarcomere lengthens, the Z lines move farther apart, and a gap appears between the two sets of actin filaments (2.5 μm in Fig. 23.3 C). When the sarcomere reaches a length of approximately 2.2 μm, there is a maximal overlap between actin and myosin filaments ^{, ,} (2.2 μm in Fig. 23.3 C). At longer muscle and sarcomere lengths, actin and myosin filaments overlap less. The maximal sarcomere length is 3.0 μm. Further elongation of the muscle occurs by slippage of fibers and not by further sarcomere lengthening. ^{, ,}

(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.)

Relationship between muscle strips and intact ventricles

With preload , stretching a muscle strip is equivalent to end-diastolic fiber length of the intact ventricle. This length can be measured by various devices in animals; however, in the intact human ventricle, it is best related to end-diastolic diameter or volume. Frequently, end-diastolic pressure has been used interchangeably with end-diastolic volume as an index of preload, but this usage can be misleading if the distensibility of the ventricle changes or if pressure outside the heart (pericardial or intrathoracic) rises.

Afterload is more complicated in the intact ventricle, commonly defined as the pressure or load against which the heart contracts to eject blood. Often, aortic systolic pressure is equated with afterload. However, in the muscle strip, afterload represents the force exerted by the muscle during contraction; in physical terms, force = pressure × area. ^, Therefore, afterload accounts for the distribution of pressure over the surface to which the force is applied. When the force is applied to a thick spherical chamber, it is more accurately described by the Laplace wall stress relationship:

where P is the transmural pressure across the wall of the chamber, r is radius of curvature, and h is wall thickness. Because the left ventricle is not a regular sphere, particularly in systole, the Laplace formula is an oversimplification. A fairly simple and accurate formula was developed by Grossman and colleagues :

Note that if the left ventricle dilates acutely, wall stress rises markedly because r gets bigger and h gets smaller.

The major findings from studies of muscle strips have been confirmed in intact ventricles. Increasing preload increases the pressure generated by an isolated ventricle that is not allowed to eject, as observed in the 20th century by Otto Frank. If the ventricle is allowed to eject, then increased preload allows the heart to eject the same stroke volume against an increased afterload or to eject a greater stroke volume against a constant afterload. This is the Starling component of the Frank-Starling law. ^, The mechanism of this response is twofold: (1) lengthening the sarcomere places the myosin and actin fibrils closer together for stronger interaction and (2) increased calcium sensitivity is mediated in some way by titin stretching. Therefore, stretching the sarcomere to its optimal length (see Fig. 23.3 C) will increase contractility. Beyond that length, further stretching (or preload) can be detrimental as the end-diastolic pressure increases without a significant change in the stroke volume. There is evidence that in failing hearts, this relationship between preload and developed tension may be absent.

The force-frequency relationship is a property of the cardiomyocyte whereby heart rate modifies contractility. Heart rates up to an optimal heart rate increase the force of contractility beyond which force decreases. The force-frequency relationship can be determined in intact hearts ^, by examining the response of the maximal rate of change of pressure (dP/dt max) in the ventricles after premature beats. The results in intact ventricles and muscle strips are similar. Subsequently, Seed and colleagues applied this technique to humans with normal or abnormal LV function and found an optimal R-R interval of 800 ms. This response is mediated by an increase in the intracellular calcium in normal hearts but is limited in the setting of ventricular dysfunction. As with preload, the force-frequency relationship may be abnormal in failing hearts. ^,

Pressure-volume loops

If LV pressure and volume are measured simultaneously, the resulting pressure-volume loop gives information about ventricular performance and can be used to assess myocardial contractility in the intact heart.

The modern approach to analyzing these loops is based on the elastance concept of Suga and Sagawa. Elastance is the ratio of pressure change to volume change (the reciprocal of compliance). Consider an isolated ventricle that can be filled to different volumes. At each volume, the ventricle is stimulated to contract and generates a peak systolic pressure ( Fig. 23.4 A). As volumes increase (1 → 2 → 3), so do the peak systolic pressures generated, and the relationship is linear (Frank’s law). The line joining the peak pressures intercepts the volume axis at a positive value, termed V ₀ , that indicates the unstressed volume of the ventricle. The equation for this line is as follows:

Concept of ventricular elastance. (A) Isolated ventricle contracting at volumes 1, 2, and 3, generating corresponding pressures. Purple line I indicates results at increased contractility. Blue line D indicates results at decreased contractility. (B) Ventricular pressure-volume loops achieving end-systolic pressures of 1, 2, and 3 at corresponding volumes. Purple line I indicates results at increased contractility, with greater end-systolic pressures at each volume. Blue line D indicates results at decreased contractility. From a given end-diastolic volume, either the same ejection fraction is delivered at a lower end-systolic pressure (dotted line 1) or the same end-systolic pressure is achieved but at a much smaller stroke volume and ejection fraction (line 4) . (C) As a consequence of afterload increase, the ventricular end-diastolic volumes (EDV) increase, then stroke volume can be maintained, even though ejection fraction decreases. If contractility is decreased (blue line) , then stroke volume can be maintained only with increasing end-diastolic pressures. 1 , 2 , 3 , End-systolic volumes and pressures at normal contractility; I , II , III , end-systolic volumes at decreased contractility; V ₀ , resting (unstressed) volume.

where P _es is end-systolic pressure, E _es is slope of the line, the end-systolic elastance or the maximum elastance (E _max ), V _es is end-systolic volume, and V ₀ is unstressed volume. If contractility increases (more calcium enters the cells), the ventricle can generate greater pressures at any given volume, thereby generating a steeper pressure-volume line (higher value of E _es ; purple line I in Fig. 23.4 A). If contractility decreases, the ventricle generates lower pressures at any given volume, and the pressure-volume line is less steep (lower value of E _es ; blue line D in Fig. 23.4 A).

The typical pressure-volume loop shown in Fig. 23.4 B is characterized by four phases marked by the opening and closing of the AV and arterial valves: diastole starts when the aortic and pulmonary valve close and the ventricular pressures fall owing to muscle relaxation; initially, with the AV valves closed, the isovolumic relaxation phase occurs since both inlet and outlet valves are closed with no change in ventricular volume. This phase is followed by opening of the AV valve when atrial pressures are higher than ventricular pressures and initiation of ventricular filling. During diastolic filling, volume increases and diastolic pressure rises slightly because of the increase in passive tension. At the end of diastole, when the ventricular pressures surpass atrial pressure, AV valves close and isovolumic contraction starts. In this phase, ventricular pressure rises with no change in volume. When ventricular pressure exceeds aortic pressure, the aortic valve opens, blood is ejected, and ventricular volume decreases. Ejection ends, and pressure falls to diastolic levels as isovolumic relaxation occurs and the cardiac cycle restarts. The decrease in volume during ejection is the stroke volume, which, divided by the end-diastolic volume, gives the ejection fraction; normally, ejection fraction is greater than 65.

If afterload is suddenly increased by raising aortic pressure, the normal heart responds as shown in Fig. 23.4 B. In the first beat after the increase, the ventricle must generate a higher pressure before the aortic valve opens ( loop 2; orange line ). It then ejects but cannot eject the same stroke volume. In fact, the end-systolic volume is that which is appropriate for the higher pressure (compare Fig. 23.4 B, end-systolic volume at 1 and 2 in the orange line ). If different afterloads are used, the end-systolic pressure-volume points define a sloping line that is the same as the line obtained in the isolated heart at those same volumes. This is the maximal ventricular elastance (E _es ) or end-systolic elastance (E _es ) line. If ventricular contractility increases, then the ventricle can attain higher ejection pressures at any given volume, and the end-systolic pressure-volume points lie on a steeper line that lies above and to the left of the normal line ( purple line I in Fig. 23.4 B). If ventricular contractility decreases, then the end-systolic pressure-volume line lies below and to the right of the normal line ( blue line in Fig. 23.4 B). Note from Fig. 23.4 B that, from a given end-diastolic volume, the ventricle with impaired contractility can either eject the original stroke volume at much reduced pressures or eject at a normal pressure only by reducing its stroke volume drastically (loop 4).

In beats that follow a sudden increase in afterload, the ventricles adjust ( Fig 23.4 C). Because of the reduced stroke volume in the first beat following afterload increase, the end-systolic volume is larger than normal. During diastole, however, a normal stroke volume enters the ventricle so that end-diastolic volume increases ( loop 2 in Fig. 23.4 C). In normal ventricles, the increased end-diastolic fiber length causes little increase in diastolic pressure. The pressures during ejection and the end-systolic pressure-volume point are unchanged, but stroke volume and ejection fraction increase. After a few more cycles, a new equilibrium is established (loop 3) in which the ventricle ejects a normal stroke volume at the higher afterload. However, the ejection fraction is subnormal because, although the stroke volume is normal, the end-diastolic volume is increased. The ventricle has adapted to the higher afterload by increasing end-diastolic fiber length, a phenomenon described by Starling and discussed by Ross ^, under the term preload reserve . If the ventricle has decreased contractility ( dashed loops , blue line in Fig 23.4 C), the same pattern of response occurs but with some important differences. With decreased contractility, the ventricle cannot eject a normal stroke volume from a normal end-diastolic volume. Compensation results in a larger than normal increase in end-diastolic volume, even at normal afterloads. Any increase in afterload causes a further increase in end-diastolic volume; this increase causes diastolic pressures to rise to high values that cause pulmonary congestion. The normal preload reserve has been used up in the attempt to eject a reasonable stroke volume against a modestly increased afterload. In more depressed hearts, even normal afterloads cannot be handled by the ventricle without a pathologically raised diastolic pressure in the ventricles or a drastic decrease in stroke volume. Note that in these hearts, because of the relatively flat slope of the maximal ventricular elastance line, a slight reduction of afterload produces a relatively large increase in stroke volume and a relatively large decrease in ventricular end-diastolic volume and pressure. This is one of the mechanisms for cardiac improvement with afterload reduction in the setting of systolic dysfunction.

The normal RV pressure-volume curve is triangular, unlike the more rectangular LV pressure-volume curve described earlier. This difference is accounted for by a relative lack of isovolumic contraction and relaxation times in the right ventricle. The normally low afterload of the right ventricle and the high compliance of the outflow portion of the ventricle allow ejection to begin almost instantaneously after the onset of contraction and proceed through pressure decline so that there is near complete emptying of the ventricle by the end of systole and the ejection time of the right ventricle thus spans the entire period of systole. An important consequence of this relationship is that even small increases in RV afterload begin to make the RV pressure-volume curve resemble the normal LV pressure-volume curve, with isovolumic contraction and relaxation times becoming more prominent. Ejection fraction is reduced, although stroke volume may be maintained due to RV dilation, and the thin-walled right ventricle may handle this new physiology quite poorly.

Assessing myocardial contractility: Systolic ventricular function

An index of contractility must reflect the ability of the ventricle to perform work independent of changes in preload and afterload. Contractility can be defined as the alterations in cardiac function that occur secondary to changes in cytosolic calcium availability or sarcomere sensitivity to calcium. Thus, β-adrenergic agonists or phosphodiesterase inhibitors, which increase cytosolic calcium, are positive inotropic agents. However, quantifying contractility in the intact heart is difficult because all indices of contractility are indices of overall performance of cardiac function and are not independent of loading conditions and heart rate. The relationship between loading conditions and contractility is complex since the handling of calcium within the myocyte is influenced by (1) the myocardial fiber length, which, in turn, depends on the preload (Frank-Starling mechanism) ; and (2) afterload, as it has been demonstrated that contractility increases in response to a rise in the afterload. Despite these limitations, the methods we currently have to assess contractility can be divided into those occurring in early systole during isovolumic contraction (isovolumic phase indices) and those that occur later, during ejection (ejection phase indices).

Ejection phase indices

The index of contractility most commonly used today is the maximal (end-systolic) ventricular elastance of Suga and Sagawa, which is defined by the slope of the end-systolic pressure-volume relationships. Measurements must be obtained at several different levels of afterload, and either ventricular volumes must be measured or echocardiographic dimensions must be used as substitutes for volumes. ^, Several studies have shown that the maximal elastance line often is not linear, as previously stated, ^, but the values of elastance in the midrange of pressures are accurate enough to use the slope of the end-systolic pressure-volume relationship as a parameter of left ventricular contractility.

The LV end-systolic wall stress-velocity of fiber shortening relation as a single beat index of contractility has also been used. This index is not exempted from limitations, which arise from the need to adjust for changes in afterload, and single-point determinations are of little use since the relationship is not linear ( Fig 23.5 ).

(A) Relationship between rate-corrected mean velocity of fiber shortening (V _cf ) and left ventricular (LV) end-systolic wall stress. (B) Possibility of misinterpreting the relationship between mean velocity of fiber shortening and end-systolic wall stress. Left, Data point 1 is more than two standard deviations (SD) above normal relation (taken from left panel), suggesting increased contractility. Data point 2 is within the normal range, suggesting normal contractility. Middle, Alternative explanation for point 1 is that contractile state is normal, but points obtained at very low afterloads follow a hyperbolic, not a linear, relationship. Right, Alternative explanation for point 2 is that contractility is decreased. However, because of the hyperbolic relationship and the low afterload, it appears within the “normal” linear range.

(A, From Colan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load-independent index of myocardial contractility. J Am Coll Cardiol . 1984;4:715–724. B, Modified from Banerjee A, et al. Nonlinearity of the left ventricular end-systolic wall stress-velocity of fiber shortening relation in young pigs: a potential pitfall in its use as a single-beat index of contractility. J Am Coll Cardiol . 1994;23:514–524.)

Echocardiographic measurements of ventricular function are most commonly used in clinical situations. These are load-dependent measurements of contractility. These techniques measure global and regional function. They can be subdivided into those that are based on dimensional and volume changes (i.e., shortening and ejection fraction, RV fractional area change) and those that are Doppler based (such as dP/dt max). M-mode–generated ejection fraction is a popular method used in children to assess LV function noninvasively. Even though it is useful, it is a load-dependent measurement and is less accurate in the setting of mitral regurgitation, dysynchrony, regional wall motion abnormalities, and LV dilation (see Chapter 31 for more details). M-mode–derived tricuspid annular plane systolic excursion (TAPSE) is also an easily derived measurement of RV systolic function. Cardiac magnetic resonance imaging can be considered as an additional imaging modality if more accurate ventricular volumes and measurements of systolic function are required.

Assessing myocardial relaxation: Diastolic ventricular function

Diastolic function refers to the rate and extent of ventricular relaxation. ^, Many forms of heart disease manifest abnormalities of both systolic and diastolic function, but one or the other form of dysfunction may predominate and impact optimal therapy.

Diastolic dysfunction results in increased ventricular diastolic pressure at normal or even low ventricular volume either from an increase in passive stiffness of the ventricles from chronic infiltrates (e.g., amyloid), myocardial scars, constrictive pericarditis, or diffuse myocardial fibrosis, or from impaired relaxation or AV dyssynchrony. Diastolic relaxation of ventricular muscle associated with rapid release of calcium from troponin and its subsequent uptake by the sarcoplasmic reticulum allows actin-myosin cross-bridges to dissociate and the sarcomeres to lengthen, permitting the ventricle to relax. Impairment of calcium removal due to abnormalities in major contractile proteins or transport processes decreases the rate and extent of relaxation. ^, Many heart diseases, including ischemia, impair calcium metabolism and diastolic ventricular function. ^{, , ,} The most common methods to assess diastolic function are invasive measurement of end-diastolic LV pressure in the catheter laboratory or noninvasively by measurements of tissue Doppler indices, ventricular inflow, and systemic and pulmonary venous Doppler profiles. Assessing diastolic function noninvasively remains challenging in children. ^, One can measure diastolic function more accurately using micromanometer-tipped catheters to assess the time constant of diastolic relaxation (Tau), which has been associated with clinically relevant events such as duration of intensive care and hospital stay after the Fontan operation. However, this primarily remains a research tool owing to complexity and expense.

Pericardial function

The parietal pericardium is a fibrous membrane that surrounds the heart and is separated from the epicardium by a thin layer of fluid. Owing to its nonelastic properties, the pericardium enhances mechanical interactions of the cardiac chambers and limits acute cardiac dilation. Thus, if the ventricles enlarge because of sudden volume load or myocardial depression, the pericardium becomes tense and restrains further enlargement of the ventricles. ^, This is seen with acute myocardial ischemia, where LV diastolic pressure can increase without much change in ventricular volume because of tension from the pericardium. In this setting, changes in the diastolic pressure-volume relationship reflect both myocardial stiffness and pericardial constraint. ^{, ,}

Transmural pressure is the difference between intracavitary and extracavitary pressure (intracardiac pressure–pericardial pressure). Pericardial pressure reflects intrapleural pressure during the respiratory cycle, which oscillates around –5 cmH ₂ O in a spontaneously breathing patient in the absence of pericardial disease. With each inspiration, the pleural pressure becomes more negative and the pericardial pressure drops, which increases cardiac transmural pressure and facilitates filling of the right heart. Mechanical ventilation increases pleural and pericardial pressure, reduces transmural pressure and impedes filling of the right heart. This reduction in transmural pressure is detrimental for right heart filling but decreases both ventricular and aortic transmural pressure, decreasing wall stress/afterload and therefore improving stroke volume. In volume-replete patients, increased intrathoracic pressure will primarily assist the left ventricle. However, this benefit may be lost or it may even be detrimental to use positive-pressure ventilation in the volume-depleted patient. This afterload reduction and a decrease in metabolic demands due to less respiratory effort are the basis of using positive pressure, either noninvasive or invasive, ventilation in the setting of heart failure. Furthermore, in those with significant work of breathing, such as patients with pulmonary edema, the inspiratory pleural pressure is likely to be much more negative than in healthy people. This serves to significantly increase LV transmural pleural pressure and potentially make the use of positive-pressure ventilation more beneficial.

Ventricular interactions

Ventricular interactions independent of humoral, neural, or circulatory effects are called ventricular interdependence and can be divided into diastolic and systolic ventricular interactions. ^, They occur because of anatomic associations between the ventricles, interventricular septum as a shared septal wall, and enclosure within the pericardium.

In normal circulation, diastolic ventricular interactions are responsible for changes in the pulse pressure during spontaneous ventilation. During inspiration, RV filling and volume increase, and the septum moves slightly toward the left, increasing LV end-diastolic pressure and decreasing LV end-diastolic volume and therefore decreasing stroke volume. These effects reverse during exhalation, increasing stroke volume. This mechanism is the basis of pulsus paradoxus in conditions that accentuate ventricular-ventricular interactions such as cardiac tamponade or asthma. In the failing right ventricle, dilation of the right ventricle pushes the septum to the left, decreasing LV volume and preload and shifting the LV diastolic pressure-volume relationship upward and decreasing cardiac output. ^{, ,} Increasing LV afterload by manipulation of systemic vascular resistance can potentially counteract septal displacement, improving ventricular-ventricular interactions and overall cardiac output. ^, In systole, due to the shared interventricular septum, the left ventricle generates 20% to 40% of RV contractility, whereas only 4% to 10% of LV systolic pressure is generated by the right ventricle. The decrease in cardiac output that occurs with acute RV failure with an intact pericardium is at least partially attributable to a decrease in systolic LV performance.

Neural control of the heart

The autonomic nervous system is the major determinant of heart rate in the normal heart, through the balance of sympathetic and parasympathetic tone. Sympathetic fibers innervate the atria, ventricle muscles, and the conduction system. Sympathetic activation releases norepinephrine through both the autonomic nervous system and humoral adrenaline from the adrenal glands. Catecholamines bind to β ₁ -adrenoceptors activating G _s proteins, which results in increased heart rate (chronotropic effect), more rapid AV conduction (dromotropic effect), enhanced contractility (inotropic effect), and faster relaxation (lusitropic effect). The parasympathetic acetylcholine fibers mainly innervate the sinus and AV nodes. Vagal effects on the heart are mostly demonstrated by changes in heart rate but minimal direct effect on myocardial contractility. Parasympathetic stimulation may have an indirect effect on inotropy by reducing effects of circulating catecholamines or sympathetic nerve stimulation. Conversely, blockade of muscarinic receptors can intensify the myocardial contractile response to sympathetic stimulation. In conscious animals, resting sympathetic tone is low, and parasympathetic tone is high. Therefore, sympathetic blockade has little effect on heart rate and myocardial contractility, whereas parasympathetic blockade causes marked tachycardia. On the other hand, many anesthetics depress the sympathetic nervous system, leading to acutely decreased contractility and bradycardia.

The carotid and aortic baroreceptors respond to changes in arterial blood pressure. Since basal sympathetic tone is usually low, inhibiting sympathetic tone by raising aortic pressure has little effect on myocardial contractility, whereas a decrease in arterial pressure causes a reflex increase in sympathetic tone, with increases in heart rate and contractility. Carotid and aortic chemoreceptors are stimulated by low partial pressure of arterial oxygen, high partial pressure of arterial carbon dioxide, and low pH, but only when changes are significant, and even then the increase in myocardial contractility is modest. The fetus seems to be less sensitive than the adult to chemoreceptor stimulation.

Innervation is not necessary for cardiac function, as evidenced by those who have undergone cardiac transplantation. The response to exercise in the denervated heart is limited and mediated by increases in circulating catecholamines and a rise in body temperature. In intact animals and humans, β-adrenoreceptor blockade blunts the heart rate increase with exercise and abolishes inotropic response.

Cardiac output

Cardiac output (CO) is the volume of blood ejected by the heart over one minute; therefore, CO = stroke volume (volume ejected per contraction) × heart rate (contractions per minute).

Cardiac output in the fetus is determined mainly by heart rate because of a limited capacity to increase stroke volume that results mainly from decreased diastolic distensibility. Consequently, fetal bradycardia is detrimental to blood flow and oxygen delivery. However, the fetal heart can respond to increased preload (Starling’s law) with increased stroke volume provided that there is no concomitant increase in afterload. Usually, infusion of fluid into an animal causes arterial pressure to rise, and the increased afterload tends to inhibit the increase in stroke volume that would otherwise occur. Immediately after birth, there is a significant increase in total body oxygen consumption and cardiac output to about twice its later values (per unit body size).

This increase has been related to an increase in adrenergic receptors stimulated by fetal thyroid hormones. In addition, because approximately 80% of the infant’s hemoglobin is in the form of fetal hemoglobin at birth, the reduced ability of this hemoglobin to unload oxygen at the tissue level compels the infant to have a higher cardiac output than the infant will have 4 to 6 weeks later. Therefore, the neonate has limited cardiac output reserve and the heart has near-maximal contractility. ^, These features make the neonate unusually susceptible to diseases that impair cardiac function. However, the Frank-Starling mechanism is intact at this time. Evidence indicates that β-adrenoceptor stimulation helps the neonatal ventricle adapt to volume loads. Thus β-adrenoceptor blockade might be expected to be much more harmful in the neonate than in the older person with minimal sympathetic tone.

Basic metabolic processes

Basal metabolic processes can be studied by measuring oxygen uptake, production of heat, or utilization of high-energy phosphates. Isolated papillary muscle and whole-heart preparations reveal that most oxygen consumed generates force (internal work). Approximately 15% is used for shortening (external work), 20% for basal metabolic processes (protein synthesis, sarcolemmal sodium-potassium transport), and 10% for activity of sodium-potassium adenosine triphosphatase and calcium-adenosine triphosphatase. The myocardium consumes approximately 8 to 10 mL oxygen/100 g muscle per minute under basal conditions. Potassium-induced cardioplegia reduces myocardial oxygen consumption, but “resting” cardiac muscle still consumes more than five times as much oxygen as does resting skeletal muscle. During maximal exercise, the myocardium may consume as much as 60 to 80 mL oxygen/100 g muscle per minute.

Cardiac energy generated by oxidizing substrates to carbon dioxide and water is both used and stored with most of the stored energy in the form of ATP. When needed, ATP breaks down to adenosine diphosphate or adenosine monophosphate and releases energy for contractile or transport processes. Substrates for energy production can be glucose, lactate, or fatty acids, with the β-oxidation of long-chain fatty acids being the preferred substrate except in the neonatal myocardium.

l -Carnitine is essential for fatty acid transport across the mitochondrial membrane. After fatty acids enter the cell, they are activated to fatty acid (or acyl) coenzyme A (CoA) compounds by palmitoyl-CoA synthetase, then linked by carnitine palmitoyl transferase I to carnitine to form acylcarnitines, thus releasing CoA. Acylcarnitines cross the mitochondrial membrane and, at the inner surface of the membrane, carnitine palmitoyl transferase II transfers the fatty acids back to CoA. The fatty acids can then undergo β-oxidation to produce ATP. Fetuses and neonates have decreased activity of carnitine palmitoyl transferase and palmitoyl-CoA synthetase. Thus, glucose, lactate, and short-chain fatty acids are the preferred myocardial energy substrates. ^, Ischemia of heart or skeletal muscle depletes carnitine, as does chronic congestive heart failure. ^, Carnitine supplementation in these states may be appropriate.

Increases in plasma fatty acid concentration in fasting or sympathetic stimulation suppress oxidation of carbohydrates by the heart. ^, Therefore, lactate consumption or extraction cannot be used as an accurate guide to cardiac metabolism unless the concentration of fatty acids is also evaluated.

ATP is usually generated by oxidative phosphorylation; however, when oxygen supply is restricted, ATP can be generated by anaerobic glycolysis. Accumulation of the byproducts of glycolysis inhibit key enzymes and interfere with further ATP production. Therefore, the myocardium is unable to build an oxygen debt without further depressing energy production and contractility. More than 30% of the myocardial mass is mitochondria, highlighting the importance of oxidative metabolism to the heart. Studies of the fetal heart in ovine models reveal that fetal ventricles and adult left ventricles have similar oxygen consumption. Because fetal oxygen content is lower, myocardial blood flow per unit mass is about twice as high in the fetus as in the adult. ^, Oxidative capacity is lower and glycogen stores and glycolytic flux are higher in the fetal heart. This may explain why the immature heart is more resistant to hypoxemia, provided that an adequate supply of glucose is available for glycolysis. The main substrates used by the fetal heart are glucose, lactate, and pyruvate, although ketones, amino acids, and short- and medium-chain fatty acids also can provide energy. For these reasons, prolonged severe hypoglycemia can seriously depress cardiac function in the neonate but is unlikely to do so in the older person.

Determinants of myocardial oxygen consumption

In 1958, Sarnoff and Mitchell found that the area under the LV pressure curve in systole (termed the tension-time index ) correlates with LV oxygen consumption; later work has found peak wall tension (or stress) to be an even better predictor because of the importance of wall thickness and ventricular dimensions to wall stress. Increases in contractility or heart rate increase myocardial oxygen consumption. However, because they decrease ventricular size and thus wall stress, effects on oxygen consumption are mitigated. Stroke volume is also a predictor of myocardial oxygen consumption. ^, This relationship can be assessed using the area within the pressure-volume loop. This approach has been extended by Suga and colleagues ^, to note that inclusion of the area representing end-systolic pressure energy ( Fig. 23.6 ) leads to a more accurate model. Subtracting contributions of basal myocardial metabolism shows that the oxygen consumption–pressure-volume area (PVA) relationship is independent of contractile state. Further studies showed that PVA-independent oxygen consumption is a function of contractility, defined by E _max . Certain interventions—for example, acidosis—made the slope of this relation between PVA-independent oxygen consumption to E _max steeper, reflecting decreased efficiency of the system.

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