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Physiology of the Developing Heart
Introduction
The heart is the first organ to become fully functional in the developing embryo, providing the circulatory system necessary for embryogenesis and subsequent fetal development when growth cannot be sustained by diffusion of nutrients. Rapid advances in genetics and molecular biology have revolutionized our knowledge of the developing embryonic heart. Furthermore, technical improvements in imaging and noninvasive physiologic recording of the early human fetus have enabled us to build on information from studies of animal models. Improved technology has also provided new insights into human cardiovascular development in disease states, and fetal responses to intrauterine challenges can be measured noninvasively. This chapter reviews current understanding of the physiology and pathophysiology of the fetal cardiovascular system and discusses current evidence for the longer-term impact of fetal adaptations on subsequent development in childhood and beyond.
Embryonic Circulation
In the chick embryo, rhythmic pulsations of approximately 50 Hz begin in the ventricle, coincident with fusion of cushions in the ventriculoarterial segment. These pulsations are insufficiently forceful to set blood in motion or to generate recordable pressures. This is because the organization of intracellular contractile proteins is incomplete at this stage, the functional contractile units are not fully assembled, and the matrix of collagen has not yet formed. Once cardiac rhythm is established, the myofibrils within the myocytes become aligned and, as the heart rate rises, the direction of flow of blood is established to provide a circulation for the growing embryo. Growth of the atriums and ventricles is associated with an increase in the rate of pulsation of the primitive heart tube. This establishes the direction of propagation of the peristaltic waves of contraction from atrium to ventricle.
Cardiac myocytes isolated from the venous sinus, atrium, and ventricle at this developmental stage in the chick embryo all exhibit automaticity with different intrinsic rates of contraction. The ventricle is slowest, at approximately 50 to 60 Hz, whereas cells from the venous sinus have the fastest rate, with the atrium being intermediate. The earliest recordings of human fetal cardiac activity were obtained using high-frequency transvaginal ultrasound at 25 days after fertilization. The mean heart rate at this stage of gestation is approximately 90 beats per minutes and regular. This most likely represents atrial rhythm. The mechanism responsible for the characteristic early increase in heart rate between the fifth and eighth weeks of gestation is uncertain but is comparable to that occurring in the chick embryo. In chicks, it is associated with the transition of the pacemaker, first from ventricle to atrium as fusion occurs between the two, and then to the venous sinus as this segment becomes incorporated into the right atrium. The precursor of the sinus node, which assumes the role of the cardiac pacemaker subsequently, forms at the junction of the developing superior caval vein with the atrium.
By 8 to 10 weeks, the mean heart rate in the human fetus varies between 160 and 170 beats/min, declining to an average of 150 beats/min at 15 weeks. After this, the rate declines progressively toward term ( Fig. 6.1 ). This pattern of change in heart rate, seen during embryonic and fetal life in the human, also parallels that occurring in the chick, in which cardiac action begins between 33 and 36 hours at a rate of 60 beats/min and increases to 220 beats/min by the eighth day of gestation.
In the human, there is little variation of the mean heart rate at any particular gestational age up to 15 weeks because the immature cardiovascular system does not rely on heart rate acutely to control cardiac output. The maximum cardiac output occurs at the intrinsic heart rate at each embryonic stage, suggesting that, as in the chick, cardiac function is optimized by the systolic and diastolic time intervals.
Alterations in heart rate significantly affect cardiac performance, and there is no compensatory change in cycle length in response to preload as is seen in the more mature heart. Human embryos die if their heart rate falls or if they experience tachycardia. This indicates that, during cardiogenesis, extremes of heart rate are not compatible with long-term viability.
Autonomic Control
The subsequent decline in heart rate after 10 weeks, and the increased variability in heart rate after 15 weeks of gestation, may be explained by a combination of maturational changes that include development of the nervous control of the heart, stresses associated with cardiogenesis, and changes in the handling of calcium by the myocyte.
Innervation of the mammalian heart is similar to that in the chick heart, consisting of parasympathetic, sympathetic, and sensory components, all of which derive from the neural crest. Although parasympathetic and sympathetic innervation of the heart occurs early during cardiac development, the time period between innervation, neuroeffector transmission, and functional neurotransmitter reactivity of both cholinergic and adrenergic receptors varies greatly between species. Functional adrenergic and muscarinic cholinergic receptors have been detected in the heart of very early chick embryos. Maturation of autonomic control has been difficult to assess in the human fetus until relatively recently, but spectral analysis of the variability of heart rate in the normal human fetus demonstrates gestation-related changes ascribed to the imbalance between sympathetic and parasympathetic neuroactivity consistent with cardiovascular maturity of the fetus.
Biophysical Properties of Fetal Myocardium
The biophysical characteristics of fetal, neonatal, and adult myocardium have been investigated in a number of mammalian species, but studies in the sheep and rabbit have provided the majority of information (see also Chapter 4 ). These studies have consistently demonstrated that active development of tension is lower in fetal than adult myocardium at all lengths, including the optimal length. In addition, in the ovine fetus, resting tension is greater than that in the adult animal.
The difference in developed tension cannot be accounted for entirely by the greater proportion of noncontractile protein per unit cross-sectional area of fetal myocardium. It may be explained in part by the different sensitivity of the fetal contractile proteins troponin and myosin to cytosolic calcium.
In the early human fetus, handling of calcium depends on diffusional gradients through the sarcolemma in the absence of a developed sarcoplasmic reticulum. Sarcoplasmic calcium adenosine triphosphatase (ATPase) is expressed in a downstream gradient along the primitive heart tube, resulting in increased contraction duration in the outlet portions of the heart. By the 38th day of gestation, the early human myocardium may be divided into primary and working functional components. The primary components are characterized by slow conduction of the cardiac impulse, owing to the low density of gap junctions and the presence of slow voltage-gated calcium ion channels. The working components, found in the atriums and ventricles, permit fast conduction through the development of gap junctions and of fast voltage-gated sodium channels. The sarcoplasmic reticulum later regulates calcium release in the cell and is known to play an important role in the frequency-dependent facilitation of the L-type calcium current in the rat ventricular myocyte.
The three major connexins, 40, 43, and 45, are present in cardiac myocytes and are developmentally regulated. Immunoconofocal microscopy has been used to compare the distribution of these within the developing mouse and human heart. In the human, connexin 45 is most prominent in the conduction tissues, connexin 40 is also abundant in conduction tissues, particularly in the Purkinje fibers and in the atrial rather than in the ventricular muscle, whereas connexin 43 is distributed in the ventricular myocardium and plays an important role in conduction across gap junctions. Knock-out mice models have increased our understanding of the pathophysiologic role of connexin diversity in the heart. This may permit the development of connexin-specific treatment strategies to treat heritable arrhythmias affecting the fetus. Chronic exposure to an adverse intrauterine environment, such as chronic hypoxemia associated with restriction of growth, or in conditions with abnormal volume loading may result in altered patterns of calcium ionic fluxes and of abnormal β-adrenoceptor stimulation similar to that identified in diseased adult myocardium.
Protein Components
Troponin
The differences between fetal and adult myocardial contractile function are, in large part, related to their regulatory and structural protein components. Different isoforms of troponin and myosin heavy chain have been identified in fetal and adult myocardium from a number of mammalian species, including humans. These are genetically programmed during early embryonic development and are modulated by specific neurohormones, including thyroid hormone. Troponin T has been studied extensively and cloned. It regulates contraction in response to the concentration of ionic calcium. Multiple isoforms have been recognized, the gene TNNT2 being identified on chromosome 1q23. Slow skeletal muscle troponin T is the predominant isoform throughout fetal life, and its switch to the cardiac form appears to define myofilament calcium sensitivity. In the human, this transition occurs between 20 and 33 gestational weeks, with only the cardiac isoform of troponin I detectable by 9 months of postnatal life. The genes coding for these two isoforms lie in close apposition but show independent tissue-specific expression, although this close arrangement may complicate investigation of mutations implicated in cardiomyopathy. A knock-out model of myocardial troponin I showed that, although affected mice are born healthy, they begin to develop heart failure by 15 days. They have an isoform of troponin I that is identical to slow skeletal troponin I, permitting survival, but this isoform disappears after birth despite the lack of compensatory myocardial troponin I. Consequently, the ventricular myocytes have shortened sarcomeres and elevated resting tension, and they show reduced sensitivity of their myofilaments to calcium under activating conditions.
β-Myosin
The β-myosin heavy chain isoform predominates in all fetal mammals thus far examined, including humans. This isoform is advantageous in the fetus because it uses less oxygen and ATP than the adult α-isoform to generate the same amount of force. Recent investigations have shown repression of fetal genes that downregulate adult, but not fetal, isoforms in response to increased cardiac work and subsequent mechanical unloading. This response appears to result in mechanical improvement and may be important in future strategies for the management of cardiac failure.
However, caution should be exercised in the interpretation of results from animal models. A review of responses of the fetal gene program in the rodent model of cardiomyopathy in diabetes indicated that the most commonly measured genes in the fetal gene program are confounded by the diabetogenic effects.
The myosin heavy chain carries the ATPase site. The enzymic kinetics of ATPase are specific for each isoform. This is important because it is the rate at which ATPase hydrolyzes ATP that primarily determines the force-velocity relationship during myocardial contraction. This partly explains the differences in active and passive mechanics between fetal and adult myocardium. The transition from fetal to adult isoforms of myosin heavy chain around birth is similar to the controlled switch from fetal to adult hemoglobin and represents stage-specific regulation of genetic expression of the proteins prior to birth. Although a number of hormones, and particularly thyroid hormone, are known to modulate the phenotypic expression of the myosin heavy chain, the factors responsible for the precise timing of the transition from fetal to adult isoforms remain unknown, although the molecular mechanisms are thought likely to be associated with the myosin heavy chain (MYH) gene cluster.
Fetoplacental Circulation
The fetal circulation has two circulatory systems arranged in parallel and characterized by five unique features that permit the delivery of oxygenated blood to the left side of the fetal heart from the placenta and direct systemic venous return away from the fluid-filled lungs and back to the placenta to become oxygenated. The placental circulation is designed to maximize exchange of oxygen and nutrients between the mother and fetus. The oxygenated blood flows in the umbilical vein into the fetal liver where a variable portion enters the venous duct. This small vessel connects the intrahepatic portion of the umbilical vein to the inferior caval vein, and the higher velocity jet streams through the oval foramen into the left side of the heart. This mechanism is essential for filling of the fetal left ventricle as the fetal lungs are fluid-filled and have a relatively low circulatory volume compared with their postnatal function. The systemic venous return from the fetal body is ejected from the right ventricle, with the majority diverted away from the pulmonary circulation through the arterial duct, into the descending aorta below the level of the isthmus. This deoxygenated blood returns to the placental circulation via the two umbilical arteries for oxygenation and receipt of nutrients.
Placenta
The placenta plays a major role in the fetal circulation, fulfilling the functions of the lung for exchange of gases, and for the kidney and gastrointestinal tract in delivery of nutrients and excretion of metabolites. The fetal side of the placenta, which develops from the chorion, receives blood from paired umbilical arteries, which take origin from the internal iliac arteries of the fetus. The umbilical arteries within the cord spiral around the umbilical vein and then divide into branches at the junction of the cord and the placenta. These branches have a radial disposition. The terminal branches perforate the chorionic plate and form anastomotic plexuses within the main stem of each chorionic villus. Each main stem possesses a derivative of the umbilical artery, which penetrates the thickness of the placenta, dividing to form a huge network of capillary plexuses. These project into the intervillous spaces that contain maternal blood. As a result, there is a very extensive surface area within each chorionic villus, across which exchange of gas occurs down gradients for both oxygen and carbon dioxide. There is essentially no mixing of maternal and fetal blood. Following oxygenation within the chorionic villuses, the blood enters the venous radicals within each main stem. These efferent venules become confluent at the junction of the placenta and umbilical cord to form the umbilical vein. The normal umbilical cord shows a regular coiling of the umbilical vein and arteries ( ) that may be altered in disease states such as hypertension (discussed later) ( Fig. 6.2 ).
Venous Duct
The umbilical vein carries oxygenated blood, with an oxygen saturation of between 80% and 90%, from the placenta to the umbilical cord ( Fig. 6.3A ). The umbilical vein enters the fetal abdomen, where it divides to form the portal sinus and the venous duct. The portal sinus joins the portal vein, while the venous duct carries oxygenated blood to the inferior caval vein ( ). The origin and proximal part of the venous duct acts as a physiologic sphincter, which, during hypoxemia or hemorrhage, results in an increased proportion of oxygenated blood passing through the duct to the inferior caval vein and to the heart, with less exiting to the portal sinus and the liver. The oxygenated blood from the venous duct can be demonstrated coursing along the medial portion of the inferior caval vein after their confluence. Flow in the inferior caval vein continues toward the inferior aspect of the right atrium, where a proportion of the oxygenated blood is slipstreamed by the lower border of the infolded atrial roof, also known as the dividing crest or “crista dividens.” This structure therefore acts as a baffle diverting blood into the atrium, a process that can readily be visualized during echocardiography ( ).
Only a proportion of the oxygenated blood is diverted to the heart, and this proportion varies in different mammalian species and in health and disease states. The remainder of the mainly desaturated blood mixes with the desaturated blood from the mesenteric, renal, iliac and right hepatic veins and with that from the coronary sinus and the brachiocephalic veins.
Oval Foramen
Patency of the oval foramen is essential to enable filling of the left side of the heart in the fetus, as pulmonary venous return is low ( ). The proportion of oxygenated blood returning to the left side of the heart also varies between species. This oxygenated blood mixes with the desaturated blood returning to the left atrium via pulmonary veins such that, after complete mixing in the left ventricle, the oxygen saturation is approximately 60%, compared with levels between 50% and 55% in the right ventricle. Blood from the left ventricle is directed to the brachiocephalic circulation, thus supplying the most oxygenated and nutrient rich blood to the brain, which grows at a disproportionately greater rate than the rest of the body in the human fetus. The majority of blood ejected into the ascending aorta by the left ventricle is directed cephalad to the head and upper limbs, and only approximately one-third of the left ventricular stroke volume crosses the aortic isthmus to reach the descending thoracic aorta and lower body ( ). Although the arterial saturation of oxygen is comparatively low, extraction of oxygen by the tissues is facilitated by the leftward displacement of the dissociation curve for oxygen of fetal hemoglobin compared with that of the adult.
Arterial Duct
The systemic venous return has an oxygen saturation of approximately 40%. This blood passes through the tricuspid valve into the right ventricle, where mixing with blood from the venous duct occurs before it enters the pulmonary trunk, where the oxygen saturation is between 50% and 55%. The majority of blood in the pulmonary trunk passes through the arterial duct to the descending thoracic aorta, with only a small proportion continuing to the lungs via the right and left pulmonary arteries. The arterial duct enters the descending aorta immediately distal to the isthmus and the origin of the left subclavian artery, and blood is directed to the descending thoracic aorta by the geometry of its insertion and also by a shelflike projection at its upper insertion ( ). The degree of patency of the arterial duct is regulated by the periductal smooth muscle cells, which produce prostaglandins. Blood from the arterial duct mixes with that crossing the aortic isthmus from the aorta. This produces a saturation of oxygen between 50% and 55% in the descending aorta, from which approximately 30% returns to the placenta via the umbilical arteries for reoxygenation (see Fig. 6.3B ).
Aortic Isthmus
The aortic isthmus is a watershed region of the aortic arch lying between the aortic arch, just proximal to the region where the arterial duct enters the descending aorta. It is the only true shunt in the fetal circulation and allows communication of the left and right ventricular outflows ( Fig. 6.4 ). Only approximately one-third of the left ventricular stroke volume crosses the aortic isthmus and thus its caliber is a little less than that of the transverse arch and descending aorta. This shunt is capable of responding to the different impedances of the placental and cerebral circulations, as well as reflecting differential ventricular performance and ejection volumes. Thus blood flow is directed cephalad in growth-restricted fetuses to provide increased delivery of oxygen and nutrients ( ) and in disease states where there is left heart obstruction or cerebral vascular steal.
Maturational Changes in the Early Fetal Heart
In vivo Studies
Diagnostic imaging of the fetal heart is possible from 12 gestational weeks, even in multiple pregnancies. Modern ultrasound transducers with limits of resolution of approximately 50 µm in the axial plane at 6 MHz and less than 100 µm in the lateral plane permit diagnostic views at normal obstetric scanning depths. As a result, morphologic and physiologic data have become easier to record and more reliable. Improved resolution should increase the robustness of calculated measures such as indexed combined cardiac output that relies on measurements of biometric variables and valve diameters. z -Scores have been derived to take account of the effects of fetal gestation and growth on the size of vessels, valves, and chambers. z -Scores are particularly useful for quantitative comparison when cardiac structures are hypoplastic, and values are available online or via a smartphone app.
New indexes reflecting the developmental abnormality of cardiac shape in various disease states have been developed including the sphericity index of the heart (most often abnormalities of fetal growth), and a 24-segment approach to its assessment has been proposed using specialized offline software ( Fig. 6.5 ).
More advanced ultrasound techniques, using three-dimensional (3D) and four-dimensional (4D) technology with shortened acquisition times less than 3 seconds and magnetic resonance imaging (MRI), permit physiologic assessment of ventricular volumes noninvasively but only where imaging is optimal. Lack of resolution of both modalities and expense of MRI have prevented their introduction into routine clinical practice.
However, a new automated program, combining color or bidirectional power Doppler ultrasound with fetal intelligent navigation echocardiography shows promise in processing 3D volume sets to generate standard views.
Postmortem Studies
The first systematic study of cardiac growth in the human fetus was made using a large series of normal hearts obtained at postmortem. This established the relationship between total body weight, total heart weight, and the change of heart weight with gestational age. However, impressive, near histologic detail has been made possible by newer technologies. There is a clinical imperative to develop techniques to achieve a “noninvasive postmortem,” and these have been investigated, both for whole body autopsy and to examine single-organ specimens obtained following pregnancy loss or termination. These techniques include high-resolution episcopic microscopy (HREM), micro-computed tomography, and high-field MRI.
High-Resolution Episcopic Microscopy
HREM is an ex vivo technique. Used more frequently to examine small animal hearts, it has been applied in the first and early second trimester human fetal heart when the small size and fragility of structures make other techniques difficult. The heart specimens are processed, embedded in plastic resin (JB4, Polyscience), and serially sectioned to produce more than 1000 sections from each heart. HREM automatically captures an image of high resolution (minimum 1 µm) from each section and compiles the serial images in perfect alignment to produce a 3D volume ( ). There are several unique maturational features of the normal early human fetal heart. On external examination at 11 weeks’ gestation ( Fig. 6.6 ), the atrial appendages are large compared with the relatively small atrial chambers, and the coronary arteries are prominent. Internally the normal off-set of the mitral and tricuspid valves is infrequently appreciated before 13 gestational weeks, and the perimembranous region and muscular part of the ventricular septum are thickened. The semilunar valves are gelatinous and poorly delaminated from the arterial walls. The arterial wall-to-lumen ratio in the first trimester fetus is threefold that of the mid-second trimester specimens. Histologic staining of the 3-µm resolution slices is feasible and provides more information about gestational changes in the normal and malformed heart. A comparison of the information available from 4D high-resolution transvaginal sonography of the first-trimester fetal heart and HREM confirms the relatively poor ultrasound detail available to us clinically at this early gestational age.
These observations suggest we continue to exercise caution in the interpretation of first trimester echocardiographic studies as 2D echo and color Doppler imaging may erroneously give the impression of valvar stenosis and narrowed outflow tracts, or of an atrioventricular septal defect.
Micro-Computed Tomography
Micro-CT provides near-histologic levels of detail in the early gestation human heart. It has exposure times between 500 and 1000 ms and produces isotropic voxel sizes between 19 and 31 µm, depending on specimen size. Similar to HREM, postprocessing techniques allow the digital removal of supporting material, and multiplanar reconstructions, to create virtual dissections of the fetal heart ( Fig. 6.7 ). It has the advantage over HREM of being nondestructive so the images can be reexamined by other specialists to provide additional diagnostic opinions (while reducing the need for transportation of tissues), and it can image larger sized specimens than HREM. It may be superior to traditional autopsy in assessment of the myocardium, and its resolution is superior to 1.5 Tesla MRI and uses far shorter imaging times, usually less than 1 hour. Current challenges include the effects of tissue coloration and distortion secondary to fixation and the use of contrast. In addition, the file sizes are very large (10 to 30 GB), and this may provide a practical barrier to its routine implementation for fetal postmortem.
Magnetic Resonance Imaging
High-field MRI at 9.4T was found diagnostically superior to conventional 1.5T less than 22 gestational weeks, but the imaging times may be as long as 18 hours to obtain resolutions comparable to those achieved by micro-CT and HREM. This is currently the main barrier to its use in postmortem diagnostic imaging of the fetus.
Physiology of the Fetal Circulation in Health and Disease
The human fetoplacental circulation shows adaptive changes that can be measured noninvasively using Doppler ultrasound and has allowed comparison with the previously reported animal studies. Initial experimental work in fetal sheep demonstrated a redistribution of flow in response to hypoxemia. With the availability of noninvasive Doppler techniques, similar information on the altered Doppler waveforms associated with abnormalities of pregnancy has been gathered. Initial studies in the human used blind continuous wave ultrasound of the umbilical cord revealed (e.g., low diastolic flow in the umbilical artery in association with uteroplacental insufficiency). While on the fetal side of the placenta, an increased resistance to flow in growth-restricted pregnancies was described. Technical improvements, including newer color Doppler modalities such as energy and directional power, have enabled the visualization and interrogation of smaller vessels in regional circulations, and indicators of fetal well-being have been derived. A comparison of Doppler waveforms in the carotid, aortic, and umbilical arteries and in the middle cerebral artery has provided evidence of redistribution of flow in the growth-restricted human fetus. Animal work has supported the concept that, in the presence of uteroplacental insufficiency, the cerebral circulation becomes the vascular bed with the lowest impedance in the fetoplacental circulation. As systemic impedance rises, flow is directed retrogradely through the arch toward the cerebral circulation. Increased flow to the brain results in a decreased pulsatility index recorded in the middle cerebral artery ( Fig. 6.8 ).
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