The Immature Heart and Anesthesia (1997)

(Baum) Associate Professor of Anesthesiology and Pediatrics, University of Virginia.(Palmisano) Associate Professor of Anesthesiology and Pediatrics, Medical College of Wisconsin.Received from the University of Virginia, Charlottesville, Virginia, and from the Medical College of Wisconsin, Milwaukee, Wisconsin. Submitted for publication September 16, 1996. Accepted for publication July 16, 1997.Address reprint requests to Dr. Baum: Department of Anesthesiology, University of Virginia Medical Center, Box 238, Charlottesville, Virginia 22906–0010. Address electronic mail to: vbaum@virginia.edu.Dennis M. Fischer, M.D., EditorThe concept that fetal and neonatal myocardia are functionally immature developed several decades ago, based on experiments showing that fetal and neonatal myocardia develop less tension per unit cross-sectional area than adult myocardium. [1–4] In addition, neonatal hearts responded less than adult hearts to most pharmacologic and physiologic stimuli, [1,3,5–7] and neonatal hearts require higher extracellular Ca sup 2+ concentrations to optimize contractility. [1,2,8–11] Similarly, the response of immature human myocardium to anesthetics differs from that of adults, and neonates appear to be more sensitive to the depressant effects of volatile anesthetics. [12–14] These characteristics can relate to differences in cellular structure and physiology.Although the advent of fetal echocardiography has made possible qualitative and quantitative measures of immature human myocardium, knowledge of specific human myocardial development remains incomplete. Complicating extrapolation of animal research to humans is the fact that late fetal cardiac development differs among species. Myocytes from rabbits, [15,16] rats, [17] dogs, [18] and cats [19] are relatively immature at birth, whereas myocytes from sheep [20] and guinea pigs [21] are relatively mature. Many programmed changes in cardiac development and control occur (Table 1), and the reasons for many of these are as yet unknown.Recent investigations into the mechanisms and regulation of cardiac function have revealed increasingly complex levels of control as our understanding has progressed from the morphologic to the physiologic and more recently to the molecular biologic level. This review will present developmental aspects of cardiac function and relate it to anesthetic effects on the immature heart. Readers interested in additional information on subcellular control mechanisms are referred to recent reviews by Lynch. [22,23]Force generation by isolated muscle strips in a variety of nonhuman species, standardized for cross-sectional area, increases during development. [1,3,7,24,25] In humans, force development in the intact fetal heart is significantly less than in the adult, and the decreased fractional shortening observed by fetal echocardiography is similar to the decreased shortening in isolated strips of nonhuman fetal myocardium. [26,27] The fetal heart has limited increases in output in response to changes in preload [28–30] and afterload. [19,28] Instead, fetal combined ventricular output increases significantly with increases in heart rate. [31,32] At birth, left ventricular output increases two- to threefold, [24,33,34] a result of alterations in preload, afterload, contractility, and heart rate. [34,35]Studies of isolated fetal muscle strips have shown that fetal myocardium cannot generate the same contractile force as adult myocardium throughout the entire range of the length-tension curve. [7,36] Optimal end-diastolic sarcomere length, perhaps the ultimate measure of preload, is age-independent. This was originally ascribed to the relative deficiency of contractile elements, but as described in later sections, immaturity of a variety of subcellular systems and limited sympathetic modulation of cardiac function may also contribute. After birth, the neonatal heart has a limited ability to increase cardiac output in response to alterations in preload or afterload, [24,37–39] probably as a result of already near maximal beta-adrenergic stimulation. Contractile reserve increases as myocytes mature, and baseline beta-adrenergic tone decreases. [24,34,37]These findings led to the claim that the immature heart is extremely heart rate-dependent, i.e., it is capable of modulating cardiac output via alterations in heart rate and is relatively insensitive to changes in intravascular volume, i.e., preload. [40] This is an oversimplification. Whether preload (the Frank-Starling mechanism) or heart rate is the primary regulator of cardiac output in the fetus and newborn remains controversial. Clearly, both mechanisms are functional.Studies in fetal and immature experimental animals have produced conflicting results. Some investigators have reported that heart rate, rather than preload, is the primary modulator of cardiac output in the immature animal, as increases in preload increase stroke volume and cardiac output minimally. [29,41] Several studies have failed to demonstrate a significant increase in right or left ventricular output in response to a volume load. [19,28,30] This may result from the fetal heart operating near the peak of its Starling curve (to be discussed). [29] There is a rate-dependent increase in contractility in immature myocardium in vitro, [42] although the mechanism for this is unknown.Others, in contrast, have reported that the Frank-Starling mechanism has primacy even in the immature heart and that heart rate changes have little, if any, effect on output. [31,43] A Doppler study in human fetuses has suggested that the Frank-Starling relationship is the prime regulator of cardiac output in the human fetus, as in adult humans. [44] The resting end-diastolic pressure in fetal ventricles is about 3–5 mmHg. The plateau of the Frank-Starling relationship in the fetal ventricle appears to be at a lower pressure than in the mature heart (Figure 1). [29] Difficulties in studying fetal cardiac hemodynamics include the involvement of the compliant utero-placental bed and the possibility that volume infusions in early studies had a secondary effect in increasing afterload by filling an already maximally dilated bed. When left ventricular afterload is controlled, increasing left atrial pressure beyond 10 mmHg increases stroke volume. [45] The neonatal animal, unlike the fetal animal, is capable of a significant increase in cardiac output in response to a volume load, although this increase is more pronounced after the first few weeks of life. [38] Clinicians recognize that anesthetized neonates routinely increase blood pressure with acute volume infusions.The response of neonatal myocardium to changes in afterload is difficult to determine because of the interrelationship of afterload and preload. At very low levels of afterload in the intact heart (as opposed to isolated muscle strips), preload is not maintained, and cardiac output decreases; thus in these studies preload must be rigorously controlled. Fetal and neonatal myocardium are more sensitive to changes in afterload than adult myocardium, and the fetal right ventricle appears to be extremely so. [19,28]Doppler studies of the human fetal heart confirm previous experimental studies in the fetal lamb, namely that the right ventricle predominates as early as the late first trimester. [26,27,46] Similarly ultrasonographic and Doppler studies of the human fetus show that right ventricular output is 60% of the combined ventricular output in late-term human fetuses, [47] similar to early work in fetal lambs. Ventricular output near term (approximately 450 ml [center dot] kg sup -1 [center dot] min sup -1) is similar in fetal humans and fetal lambs. [41]Diastolic function, particularly as it relates to anesthesia, has recently been reviewed. [48,49] The diastolic characteristics of the heart relate not only to sarcomeric diastolic function, but also to passive stretch properties of the cytoskeleton, intercellular matrix, ventricular interaction, and pericardium. Compliance of isolated myocardium and intact ventricles increases with maturation. [3,7,25,36,50] Both -dP/dt (the change of pressure with time during diastole), a measure of early relaxation, and tau (the time constant of isovolumic relaxation), a measure of later diastolic filling, are decreased in neonatal hearts compared with adult hearts. [51] Measurements of tau may be more relevant at the rapid heart rates of young animals because relaxation from the previous systole will typically not have any effect on end-diastolic pressure at heart rates of less than 150–160 beat/min. [52]The findings of decreased diastolic compliance in isolated nonhuman fetal myocardium have been confirmed in Doppler studies of human fetuses. [53,54] In addition to intrinsic properties of immature myocytes and connective tissue, the lung-chest wall and the pericardium limit right and left ventricular filling in the fetus in vivo. [55]Relaxation of the myocardial cell requires diffusion of Ca2+ from troponin C. If sarcoplasmic Ca2+ is not rapidly reduced by the sarcoplasmic reticulum (SR), uptake, then relaxation, will be limited. Thus the poorly developed SR in immature myocardium (to be discussed) may have an important role in the impaired lusitropy (myocardial relaxation) of fetal hearts. The large surface-to-volume ratio in immature cells may permit a greater role of sarcolemmal removal of Ca2+ than in more mature cells. Most of the Ca2+, at least in mature cells, is removed by the Na sup +-Ca2+ exchanger, [56] and neonatal cells have more exchanger protein, as described below.Ryanodine, an inhibitor of SR function, inhibits relaxation. Relaxation is inhibited to a greater extent in mature, than in immature, hearts, again consistent with the functional immaturity of the SR in young hearts. [50] This suggests that alternative mechanisms for the removal of Ca2+ are relatively more important in immature myocardium. The affinity of troponin C for Ca2+ would also be a factor in determining relaxation and may relate to the developmental changes in troponin I and troponin C during maturation. It has been suggested that mitochondrial Ca sup 2+ uptake is greater in the newborn rabbit than in the fetus and adult. [1]Both ventricles interact via the common ventricular septum. Increases in right ventricular pressure or volume can inhibit left ventricular diastolic filling. A decrease in right ventricular preload or an increase in right ventricular afterload may increase left ventricular filling, affecting cardiac output. [35,57]Myocardial metabolism differs between immature and mature myocardium. In vivo, myocardial O2consumption in newborn sheep and rabbits is higher than in adults and is associated with greater myocardial blood flow. [51,58,59] Higher O2consumption in newborns is commensurate with increased cardiac work (estimated as the rate-pressure product). Matching of coronary flow to O2consumption is similar between age groups, as evidenced by similar O2extraction ratios.Developmental changes in mitochondrial ultrastructure parallel changes in myocardial substrate use. The most important source of energy to the adult myocardium is long-chain fatty acids. The enzyme responsible for the transfer of fatty acids into the mitochondrion is carnitine palmitoyl CoA transferase. Activity of this enzyme is decreased in immature myocytes. As a result, the primary energy substrates in immature myocardium are lactate and carbohydrate, [58,60] thus explaining, at least in part, mitochondrial-dependent age-related increases in aerobic metabolism.Developmental changes are also evident in pacemaker and conduction system cells. Neonates have a higher intrinsic rate of sinus node automaticity, but the basis of this has not been delineated. Sinus node action potential duration also increases with age. In one study, maximum diastolic potential was significantly less negative (closer to threshold) in infant rabbits than in adults, [61] but in another study, this was not the case. [62] Threshold potential did not differ between infants and adults. [61,62] Neonates have a shorter atrioventricular (AV) conduction time that increases with maturation as a result of increases in intraatrial and His-ventricle conduction times. [63,64] AV nodal conduction time, however, is not different between neonates and adults. Although infant and adult AV nodes are morphologically distinct, their action potential (AP) characteristics are similar. [63]During the fetal and early newborn periods, the heart grows by hyperplasia (increasing cell number). After this period and throughout the rest of its life, the heart can increase mass in response to demand for increased pumped volume or increased pressure only by myocardial cell hypertrophy. [65,66]Myocardial cells (cardiocytes) change their gross appearance and their ultrastructural components during development. Cardiocytes in the very immature heart are initially smooth and rounded, changing to rod-like in the maturing cell. With continued development, the cell shape becomes irregular and develops intercalated discs, with their associated gap junctions. In humans, gap junction genes are expressed by 15 weeks of gestation. [67] Relative to total heart weight, there is more connective tissue and less contractile tissue in immature myocardium. Sarcomeres comprise 30% of fetal heart in contrast to 60% of adult heart. The surface area-to-mass ratio is greater in immature cells [68] as is the water-to-collagen content.Whereas mature cardiocytes contain parallel myofibrils within each cell, the immature myocytes have a smaller fraction of myofibrils, [1,2,7,16,20] which are less organized and may not be arranged parallel to the long axis of the cell. [15,20,65] With development, myofibrils align with the axis of the cell but lie at the periphery of the cell surrounding centrally located nuclei and mitochondria. Later, myofibrils distribute throughout the cell, as in the adult configuration.Known maturational changes in the SR are thought to be a primary explanation for differences in contractility and in Ca2+ responsiveness of neonatal versus adult myocardium. The sarcoplasmic reticulum of the immature myocardial cell is markedly underdeveloped as compared with mature myocardial cells (Figure 2). [15,16,69,70]T-tubules are invaginations of the sarcolemma of ventricular, but not atrial, cardiac myocytes that extend longitudinally within sarcomeres, allowing for more direct contact of the sarcolemma with subcellular structures lying at a distance from the cell surface. This allows for simultaneous transmission of the AP, with its associated ion shifts, to all parts of the cell, facilitating rapid activation of the entire cell. T-tubules are a requirement, therefore, of larger cells. [71] The state of the t-tubule system at birth is species-dependent. Species that have mature myocytes at birth, such as the guinea, pig have well-developed t-tubule systems, whereas those animals born with relatively immature myocytes, such as the rabbit, do not.Mitochondria develop in absolute size and relative intracellular volume during myocardial cell development, [16,18,20,72] which may continue into the postnatal period. [16,20] In addition, the intramitochondrial cristae lengthen and become more compact.An intracellular construction of microtubules and microfilaments links the contractile filaments, the t-tubules, sarcolemma, mitochondria, and nuclei. This structure, composed predominantly of the proteins titin and actinin, determines cell organization and size and allows the force of contraction to be applied to the myocyte. Developmental changes in the organization of the intracellular organelles probably reflect, and are mediated by, changes in the cytoskeleton, [73] but are largely undefined.Studies at the subcellular level indicate that Ca2+ mechanisms that activate contraction in the immature heart (which lacks a well-developed SR) derive Ca2+ primarily from extracellular sources. The various sub-cellular mechanisms such as ion channels, exchangers, and pumps (Figure 3) are optimized to achieve this end.Major Mechanisms. Although Ca2+ entering via the Ca2+ channel contributes to maintenance of the AP plateau, it has a critical role in supplying Ca2+ directly and indirectly to support excitation-contraction coupling. Because of the long-known relative immaturity of fetal SR, the sensitivity of immature myocardium to Ca2+, and of the exaggerated dependence of neonatal myocardium on extracellular Ca2+ to maintain inotropy, [8] sarcolemmal Ca2+ channels have been an area of interest in developmental cardiac electrophysiology. Although the current-voltage relationship for the major, large (L-type) Ca2+ current, ICa,L, is similar in immature and mature ventricular myocardium, [74] the kinetics (the time-dependent changes in channels allowing entry or exclusion of ions) of this channel, and its subunit composition, vary with development in the rat and rabbit, where it has been particularly studied. [75–79] This may account, at least in part, for the different pharmacologic properties of neonatal and adult Ca2+ flux. The smaller T-type Ca2+ current (ICa,T) is less prevalent in neonatal myocardium. [74]The primary function of ICa,L in mature myocardium appears to be activation of the SR Ca2+ release channel with consequent release of large amounts of Ca2+ that have been stored in the SR, so-called Ca2+-induced Ca2+ release, [80] which in turn supports contraction. In immature myocardium, ICa,L likely contributes more directly to activator Ca2+, which probably explains the well-known sensitivity of neonatal hearts to the depressant effects of clinically used Ca2+ channel blockers. [81–83] Verapamil, for example, although efficacious in terminating supraventricular tachycardia, is contraindicated during infancy for this reason. [84,85] After cardiopulmonary bypass, neonates are more sensitive to the depressant effects of rapid infusions of platelets and fresh frozen plasma, presumably as a result of chelation of Ca2+ by the citrate anticoagulant in the plasma fraction of banked blood. Citrate has known direct Ca2+ channel depressant action, and this depressant effect can be prevented or reversed in the laboratory, and clinically to a great degree, with additional Ca2+. [86] Although ICa,L is of clear and increased importance in immature myocardium, a number of lines of evidence suggest that immature myocardium requires Ca2+ source(s) in addition to ICa,L to generate tension:1. Isolated neonatal cardiac myocytes contract in the presence of a Ca2+ channel blocker. [87,88]2. Force of contraction of neonatal rabbit right ventricular papillary muscles is unaltered by the Ca2+ channel agonist BAY K8644. [89]3. Although some Ca2+ entering the cell via ICa,L may bind to the contractile apparatus, the magnitude of this Ca2+ is, in itself, inadequate to support contraction. Ca2+ entering via ICa,L is estimated to result in only approximately 10% of the Ca2+ available for tension generation in the adult myocardial cell and would result in far less than the 1.4 micro Meter required for 50% myofilament activation in neonatal myocardium. [75]4. The contractility-voltage relationship of isolated neonatal cells is linear, rather than mirroring the parabolic shape of the ICa,L current-voltage relationship. [11]5. Ca2+ current (ICa,L) increases throughout development [75,76,90,91]6. Density of Ca2+ channels also increases, [74,76,90,92,93] although there are some species differences. [77](The predominant L-type Ca2+ current, ICa,L, has recently been evaluated in atrial myocytes from children 3 to of age. The of ICa,L is lower than that reported in adult atrial myocytes, although it not change with age within this age for an alternative Ca2+ to immature myocardium has primarily on the Na sup +-Ca2+ The Na sup +-Ca2+ exchanger as the primary mechanism for Ca2+ from the cell after each allowing for diastolic relaxation. Because Na sup are for each Ca2+ the current is and to The force for this flow is the Na sup the exchanger is reversed at the AP peak and plateau, allowing Ca2+ entry into the and and that cardiac Na sup +-Ca2+ would be greater in immature myocardium, and this has been there is an decrease in Na sup +-Ca2+ during development of the and Na sup +-Ca2+ exchanger is to higher in late-term fetuses and neonates than in adults in rabbit and exchanger current is also higher in neonatal rabbits, which have a poorly developed sarcoplasmic reticulum at birth, than in neonatal guinea which have a more mature sarcoplasmic reticulum present at exchanger is located in the sarcolemma in neonatal and fetal rabbit myocardium. After the development of the to increased Ca2+ control by the the exchanger is associated with the t-tubules, as it is in mature myocardium. In addition, the AP duration in immature myocardial cells would entry of Ca2+ via the Na sup +-Ca2+ A study in humans, hearts at and weeks decreased of Na sup +-Ca2+ exchanger compared with adult contraction and intracellular in neonatal rabbit ventricular myocytes. estimated that Ca2+ via the Na sup +-Ca2+ exchanger for only 60% of the increase in intracellular Ca2+ with contraction far more than the in adult it appears that on Ca2+ entry via Na sup +-Ca2+ a significant from the variety of subcellular systems maintain an to maximal entry of Ca2+ via the exchanger and L-type channel, and effect of that in excitation-contraction intracellular Na sup is for Ca2+ by the Na sup +-Ca2+ exchanger, an Na sup is The Na sup sup sup sup energy from to maintain an Na sup the The Na sup sup the for the cardiac such as molecular of this subunit in and humans, and increases with maturation in and The functional importance of these maturational changes is not but it is of interest that children to require higher plasma concentrations of than do adults and these higher plasma concentrations by Na sup sup increase intracellular Na sup and thus decrease Na sup Ca sup in higher intracellular Ca2+ levels and presumably increased There is an increased effect of these in the fetal and neonatal rabbit compared with the adult, consistent with a role for the Na sup +-Ca2+ exchanger in modulating in the immature sarcolemmal Na sup sup exchanger the Na sup the sarcolemma to sup of the cell, although its to intracellular is not Na sup sup is greater in than in adult, rabbit and rat hearts. This may the greater function during and the greater from an of the neonatal myocardium. In addition, increased Na sup sup during may decrease the Na sup more Ca sup Ca2+ pumps Ca2+ from the to maintain an extremely low that of extracellular Ca2+ pumps in the sarcolemma Ca2+ from the cell, whereas a lower located in the of such as sarcoplasmic Ca2+ into the SR SR of the immature myocardial cell is functionally and morphologically underdeveloped in immature myocardial cells. that Ca2+ release by the SR is in fetal and neonatal myocardium. The number of Ca2+ Ca2+ uptake, Ca2+ release, the of the Ca sup 2+ and the of the Ca2+ increase during maturation in rabbits, guinea [50] and with the role of SR in immature myocardium, Ca sup 2+ of the SR by has its most pronounced effect on contraction in the adult, less in the and least in the mature myocardium, the SR has and The SR the sarcolemma at the cell surface or at the a Ca2+ protein, is located within the SR and large of Ca2+ but with low allowing maximal but and with of SR Ca2+ release channels increases with cardiac maturation. various parts of the SR are by of SR, which are in Ca2+ pumps and a that is first expressed at the time of the first of the heart. inhibits the SR Ca2+ the rate of Ca2+ within the of by one of and thus cell relaxation. At least one of is developmental of these in response to beta-adrenergic and thus are at which can a is decreased in the SR from fetal and only low levels of are expressed in human neonatal atrial myocytes. the immature myocardium was reported to Ca sup Ca2+ release, a recent study of human atrial myocytes that Ca2+ Ca2+ release SR appears in these cells by age 3 (the age however, the rate of release increased with increasing maturation. ultrastructural differences between atrial and ventricular myocytes, to ventricular myocytes is human ventricular myocytes have not been variety of developmental changes in the contractile the and of Ca2+ sensitivity with cardiac maturation. of these proteins can be expressed as several that differ in and in is by species and cell atrial and is by physiologic or the development of the most contractile protein, approximately 60% of It is responsible for energy into is composed of and of The of the are to the The of the to with and contain the that contributes to shortening with contraction. The increasing tension developed by myocardium with increasing age with increasing of can be into each of The has the The and a is and the has the Because is associated with maximal shortening of the changes in have physiologic In all species of fetal the This is to the fetal myocardium as the less to develop the same The development of is species-dependent. In the human the is the most fetal at weeks after birth, and after the of such that is predominant in adult life. with its is primarily appears that developmental regulation of is at the level and at least in part, for the very rapid of the left ventricle by in for an in neonates and infants with of the great In rats, or a of and in a from the to the as early as 3 after of increased In