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 ).
Umbilical Cord Flows
The pulsatility index was derived in the 1970s to quantify waveforms in the umbilical cord and assess fetal compromise. Abnormalities of flow in the cord are characterized first by a reduction, and then a reversal, of diastolic velocities, thus increasing the pulsatility index. A meta-analysis of subsequent studies has confirmed umbilical artery velocity measurements to be useful measures of fetal well-being, and arterial and venous Doppler waveforms have become incorporated as standard measurements in surveillance of the high-risk pregnancy, with the latter shown to provide a more specific predictor of fetal compromise ( Fig. 6.9 ). Of the Doppler measurements used in evaluation, absence or reversal of end-diastolic flow in the descending aorta or umbilical artery of the fetus is seen first and may be tolerated for a period of weeks in the compromised growth-restricted fetus, but once changes are seen in the systemic veins, emergent delivery is often the most appropriate management.
When placental function is severely reduced, as in fetuses with restricted growth, increased placental resistance leads to a reduction in total delivery of arterial oxygen to the fetus because of the reduction in mean placental return, even though the content of oxygen of the umbilical venous blood is often near normal. It is vital to examine other vascular beds in the human fetus as the fetal brain, heart, and adrenal glands respond to this pathologic state by drawing increased flow, thus requiring an increase in combined ventricular output to provide it. In the human fetus, the brain is the largest organ, and the healthy responsive fetus is able to reduce cerebral resistance by arteriolar dilation. This has led to the adoption of the ratio of the cerebral to placental resistances as both an indicator of poor fetal growth and an independent predictor of intrapartum fetal compromise.
Flow in the Venous Duct
The venous duct occupies a unique physiologic position as a regulator of oxygen in the fetoplacental circulation. Animal studies first demonstrated streaming of oxygenated blood from the umbilical vein through the oval foramen into the left side of the heart, estimated at half of the returning flow. The degree of shunting in the human fetus is less, being estimated at between one-quarter and two-fifths. The determinants of shunting include the differing resistances of the portal vasculature and venous duct, along with other influences such as blood viscosity, umbilical venous pressure, and mechanisms of neural and endocrine control. The waveforms measured within the venous duct have been found to remain normal for long periods during placental compromise, reflecting its essential role in the fetal circulation. Patterns in the umbilical vein also act as a barometer of fetal well-being. These are caused by the dilation of the venous duct in response to fetal hypoxemia that reduces impedance and allows pressure waves to travel in a retrograde fashion from the right atrium to the umbilical vein resulting in venous pulsations. Absent or reversal of flow in the venous duct is usually an ominous sign ( Fig. 6.10 ). It reflects fetal hypoxemia and has been shown to predict fetal death or adverse perinatal outcome. and usually prompts emergency delivery by cesarean section. An alternative etiology for absent or reversed end-diastolic flow in the venous duct is increased central venous pressure, seen particularly where there is obstruction within the right heart, such as pulmonary atresia with severe tricuspid regurgitation ( ). This may also result in fetal hydrops and intrauterine death.
Flow to the Brain
Doppler waveforms signifying normal brain flow in the middle cerebral artery are characterized by an expected peak systolic velocity (in centimeters per second) of approximately twice the fetal gestational age and a positive diastolic tail (see Fig. 6.8A ). Abnormality of the Doppler waveforms signified fetal hypoxemia, but initial reports that flow waveforms in the anterior cerebral artery were better able to predict adverse neurodevelopmental outcome have not been substantiated. In sheep studies the pulsatility in the middle cerebral artery was found to correlate poorly with peripheral vascular resistance, but the clinical application of the cerebral to placental resistances in the human fetus remains a subject of debate.
One of the most practical applications of the middle cerebral artery measurement is in the noninvasive detection of fetuses with anemia, where an increase in the peak systolic velocity with normal diastolic velocity has been described. The velocity is proportional to the reduction in hematocrit and directs management decisions to provide life-saving fetal therapy intrauterine transfusion.
In fetuses with intrauterine growth restriction, a “brain-sparing” phenomenon comprising increased diastolic velocities in the middle cerebral artery, producing a low pulsatility index, has been described (see Fig. 6.8B ). At delivery, brain sparing was associated with hypoxemia and abnormal systemic venous flows with acidemia and adverse perinatal outcome. Growth-restricted fetuses with abnormal venous flow have worse perinatal outcome compared with those where the abnormality in flow is confined to the umbilical or middle cerebral arteries. In fetuses with low middle cerebral arterial pulsatility, an abnormal systemic venous Doppler signal indicates further deterioration. A combination of Doppler indexes, shown to be predictive of the optimal time for delivery of the sick fetus, has been studied to identify whether they are predictive of early cerebral injury, when combined with imaging techniques. Evidence of cerebral redistribution, as measured by the ratio of the pulsatility indexes of the umbilical artery to the middle cerebral artery, was associated with reduced total volume of the brain.
Autoregulatory arterioles are sensitive to the local concentration of metabolic products but will not function if the surrounding tissue is metabolically inactive. This may misleadingly manifest as a “normalization” of cerebral Doppler flow waveforms in terminally sick fetuses just prior to their intrauterine death.
However, newer techniques using MRI may be able to provide noninvasive in vivo assessment of fetal cerebral metabolism and its response to adverse intrauterine conditions and congenital malformations. Blood oxygen–dependent MRI measures the relative state of oxygenation in the fetus by comparing the differencing magnetic properties of the oxygenated and deoxygenated hemoglobin. This can be detected using T2-weighted imaging and has been evaluated in both sheep and human studies.
Indeed, recent studies have reported a 10% reduction in oxygen saturation in the ascending aorta in fetuses with complex cardiac defects, not accompanied by the anticipated increased volume flow or oxygen extraction. This suggests that, in cardiac disease, cerebral oxygen delivery and consumption is reduced. Although it appears that the brains of fetuses with congenital heart defects develop at lower oxygen tension, the impact of this on delivery is more difficult to measure. Glucose delivery to the brain plays a vital role in its homeostasis, as does the role of chronicity of the altered state. Work in animal models suggest responsiveness diminishes with chronicity and the human fetus may adapt and downregulate the brain’s requirement for oxygen and metabolic substrates. This metabolic alteration may alter gene expression and reduce mitochondrial respiration affecting important regulatory neurohormonal axes (such as the hypothalamic-pituitary axis) and the usual pattern of brain development such as myelination resulting in its permanent alteration.
Flow Across the Aortic Isthmus
Only approximately one-third of left ventricular output, or one-tenth of total cardiac output, flows through the aortic isthmus. One consequence of this is that the isthmal diameter is smaller than that of the transverse arch and shows a characteristic Doppler pattern ( Fig. 6.11 ). Experimental increases in systemic impedance in the lamb, mimicking placental insufficiency in the human, have been shown to reduce or stop isthmal flow. In the human, where flow to the brain is 8 to 10 times that of the lamb, the hypoxic-mediated increase allows a reduction in cerebral impedance, with reversal of flow about the aortic arch that can be demonstrated on pulsed wave Doppler.
The alteration in Doppler flow profile in the isthmus in response to alteration of cerebral and placental impedances has been characterized by five separate profiles termed the isthmic flow index ( Fig. 6.12 ). Latterly the same group has developed a quantifiable index, the isthmic systolic index, to describe the influence of right and left ventricular performance on the Doppler waveforms measured in this region. The index becomes negative during the final weeks of pregnancy, where retrograde isthmic flow is common and correlates with right ventricular output. This explains the common finding of reversed flow in the transverse aortic arch in later gestation, attributable to the fall in cerebrovascular resistance, driving blood retrogradely through the isthmus during systole. The metabolically active brain responds by vasodilation resulting in an increase in the proportion of left ventricular stroke volume going to the brain, thereby reducing this retrograde flow. A plausible alternative explanation is that the fall in cerebrovascular resistance and increased cerebral flow toward term results in increased right heart preload with a subsequent increased ductal flow, leading to retrograde flow about the isthmus. Animal studies suggest that ventricular ejection times of both ventricles are similar, but these findings may not be applicable in the human fetus because the proportion of cardiac output supplying the brain is relatively greater than most experimental animal species. It is true that the opening time of the pulmonary valve exceeds that of the aortic valve due to the longer electromechanical time interval of the right ventricle, but the isthmal flow depends also on the compliance in the pulmonary vasculature (see section later). The higher the right ventricular output, the greater the reversal of branch pulmonary flow and therefore the more negative the end-systolic velocity should be producing greater reversal of transverse arch flow.
The ability of the isthmus to function as a true shunt explains why reversal of flow in the transverse arch is often seen in the healthy near-term human fetus. It also explains the pathophysiologic mechanisms underlying the reversed aortic arch flow due to the steal phenomenon in cerebral arteriovenous malformations, such as vein of Galen malformation ( ). However, interpretation of the isthmic systolic index in cardiac defects remains more complex and utility of this index requires determination.
Flow of Blood to the Lungs
The flow of blood in the lungs of the normal human fetus has been calculated noninvasively from the difference in estimated volumes in the arterial duct and in the pulmonary trunk using Doppler ultrasound. In this way, an increase with age for pulmonary flow from 13% to 25% has been described in a cross-section of normal fetuses studied from 20 to 30 weeks of gestation, and an increase in the proportion of the cardiac output from the right side to 60% at term. Pulmonary vascular resistance increases during the last trimester. This again changes the balance of the cardiac output, increasing flow into the systemic circulation. The Doppler waveform of the branch pulmonary arteries is characterized by a sharp systolic upstroke with a short acceleration time and reversal of flow in late systole ( Fig. 6.13 ). Studies have correlated these findings with pressure and circulatory events in fetal lambs and attribute the reversal of flow to the low compliance of the branch pulmonary arteries and high pulmonary vascular resistance in the fetus.
Optimal perinatal planning requires the prediction of important fetal pulmonary hypoplasia, both to aid counseling of parents and to prepare the resources required for neonatal resuscitation and support. Early echocardiographic ratios, such as the ratio of sizes of the lungs and head, were derived to predict pulmonary hypoplasia in cases with diaphragmatic hernia. A ratio less than 0.6 was associated with poor outcome, whereas a ratio greater than 1.4 predicted survival. Alternative indexes of the ratio of fetal lung volume to fetal body weight using MRI in combination with ultrasonography have been devised. Others have used MRI alone to assess the total lung volume by comparing the signal intensity of lung to that of spinal fluid. MRI and ultrasound are complimentary imaging methods for predicting fetal pulmonary hypoplasia and the prognostic accuracy of observed-to-expected MRI fetal lung volume and observed-to-expected ultrasound lung-to-head ratio have been published. Both methods have shown comparable ability to assess lung volumes in left sided diaphragmatic hernia, particularly before 32 gestational weeks, although the ultrasound method overestimates lung size by 1.5 to 1.8 compared with MRI methods. However, neither were useful predictors of outcome in right-sided lesions. Doppler parameters such as the pulsatility index have not been found discriminatory for pulmonary hypoplasia and prompted investigation of physiologic testing of the fetal pulmonary bed. Maternal hyperoxia testing studies have attempted to determine whether the near-term fetus with certain congenital defects such as diaphragmatic hernia or hypoplastic left heart syndrome can respond to a 15-minute administration of 100% oxygen delivered to the mother via facemask by increasing pulmonary blood flow.
Interpretation of the results of acute administration of oxygen are made difficult by technical considerations such as ensuring accuracy of placement of the Doppler sample volume so that the same part of the pulmonary tree is sampled before and after oxygen administration. This imaging is particularly challenging in the setting of diaphragmatic hernia.
Much uncertainty exists around the role and efficacy of chronic administration of oxygen to the pregnant woman. Long-term maternal administration of oxygen by facemask for 6 or 8 hours a day over several weeks is thought to increase pulmonary venous return in responsive fetuses, and this in turn may promote growth of left-sided heart structures in borderline left hearts or those with aortic coarctation. Although a plausible theory, outcomes have been less than convincing, and more research is required to establish, for example, the effects of chronic oxygen administration on the fetal retina, and to provide a robust evaluation of its cardiovascular effects above natural history outcomes. Little is yet known of the determinants of responsiveness in the second and third trimester fetus.
Coronary Arterial Flow
In normal fetuses, flow in the coronary arteries is not usually seen until the third trimester. Reference ranges for velocities have been described and do not appear to change with gestational age in the structurally normal heart. Visible flow was first described in terminally sick fetuses and proposed as an additional predictor of adverse outcome ( ).
Fetal ultrasound may also demonstrate visible coronary arterial flow in conditions associated with restriction of growth, anemia, constriction of the arterial duct, twin-twin transfusion syndrome (TTTS), and bradycardia, thus demonstrating short-term autoregulation and long-term alterations in myocardial flow reserve in the human fetus. It can be demonstrated in growth-restricted fetuses earlier in gestation than in appropriately grown fetuses and at higher velocity. Fetuses with anemia show the highest velocities in the coronary arteries, perhaps reflecting increased left ventricular output due to a reduction in cerebral impedance in response to both pathologic situations ( Fig. 6.14 ). Coronary arterial flow is no longer visible once the underlying cause has been treated, for example by intrauterine fetal transfusion for anemia, or by stopping any causative medication such as indomethacin in the case of constriction of the arterial duct.
Animal studies of myocardial flow show that coronary reserve is mediated by nitric oxide and changes during hypoxemia. This finding has been termed fetal cardiac sparing. Accordingly, visible flow in the coronary arteries is attributed to an increased volume of flow secondary to low fetal arterial content of oxygen.
Visualization of coronary flow coincides with important increases in the Doppler velocity z -scores in the umbilical artery, inferior caval veins, and venous duct. The greatest change was observed in the venous duct z -score occurring 24 hours before visible coronary arterial flow was identified. These changes were associated with adverse perinatal outcomes.
Developmental Changes in Cardiac Function
The ability to assess fetal cardiac function has improved as imaging techniques have advanced. Moreover, the potential for fetal therapy for certain conditions, such as semilunar valve stenosis, TTTS, and diaphragmatic hernia has stimulated a more comprehensive assessment of fetal cardiovascular function to guide their timing and monitor their success.
In the early embryo, gradients across the atrioventricular orifices act as a resistance to, and regulate, the flow of blood, thus influencing ventricular development. As the ventricular mass becomes trabeculated, so its mass increases and stiffness decreases, thus optimizing ventricular filling and ejection. Increasing cardiac efficiency is associated with increasing myocardial mass and competence of the atrioventricular and arterial valves.
Diastolic Maturation
Atrial pressure exceeds ventricular pressure throughout filling, and from early gestation there is a clear distinction between the so-called passive and active filling phases, referred to as the E and A waves, respectively. The terms are misleading because we have long recognized that early diastole is an “active” relaxation, but the terms persist in common usage. Active velocities are higher than passive velocities in the fetus and in the newborn period, resulting in a ratio between the E and A waves that is less than 1.
Transvaginal Doppler ultrasound of the human fetal heart has confirmed that ventricular inflow waveforms are monophasic before 9 weeks of gestation, becoming biphasic by 10 weeks. The patterns of ventricular filling change with age, with a relative increase in early diastolic filling, represented by the E wave, compared with the late diastolic component, or A wave, suggesting improved ventricular relaxation. Reference ranges between 8 and 20 weeks of gestation show a greater volume of flow passing through the tricuspid than mitral valve at all gestational ages. The E/A ratio is also highly dependent on preload. It cannot provide a load-independent assessment of ventricular function. It is therefore a particularly unsuitable measure in fetal life, when direct pressures cannot easily be measured, and there is debate about the interpretation of longitudinal studies. Although patterns of ventricular filling—monophasic compared with biphasic—have been proposed as more simple barometers of diastolic function, these have failed to correlate with changes in downstream impedance.
Maturational changes in ventricular properties in human fetuses accelerate after mid-gestation as diastolic filling increases mainly after 25 weeks. They are associated with a decrease in the ratio of the area of the myocardial wall to the end-diastolic diameter of the left ventricle. Thus the decrease in left ventricular wall mass related to gestational age may be one important mechanism responsible for the alterations in diastolic properties noted in the fetal heart. These are coincident with the reduction in placental impedance associated with normal adaptation of the spiral arteries.
Atrioventricular valvar regurgitation is a common finding from 9 weeks onwards. Tricuspid regurgitation is commonly found in the first trimester and is thought to be more common in fetuses suffering from aneuploidy, particularly trisomy 21. It has been incorporated into early screening programs and is used to adjust the age-related risk for trisomy 21. It is not clear why tricuspid regurgitation is more common in these fetuses but may be associated with delayed development of the atrioventricular cushions because it resolves spontaneously in most cases and has no physiologic consequences later in pregnancy or after birth. Most cases of tricuspid regurgitation reported in later gestation are also transient and trivial. They are associated with a normal outcome.
Systolic Maturation
The second half of pregnancy is associated with an increase in mean velocities through the outflow tracts and a decrease in isovolumic relaxation and contraction times. The ventricular stroke volume rises, and the afterload reduces, which is more pronounced on the left side of the heart. The peak velocities in the ascending aorta are generally higher than in the pulmonary trunk, and the gestational increase is linear in longitudinal studies. Cardiac output is traditionally calculated from the right and left ventricles using the velocity time integral of the maximum velocity envelopes through the valves, and a static assessment of valvar diameter measured at the hinge points. The mean total cardiac output calculated in this way is approximately 550 mL/min per kg body weight. However, the range considered to be normal is so wide as to make its interpretation difficult, except in serial assessment. Various investigations in humans, supported by animal data, have shown right cardiac output to be greater than left by at least two-fifths. The major source of error in the calculation of cardiac output results from measurement error of the diameter of the vessel, particularly for clinical studies, and failure to account for pulsatility of the vessel in the equation. In one study, the upper 95% confidence limits for intraobserver variation were reduced to 0.04 and 0.09 mm for diameters of 0.6 and 6 mm, respectively, by making six repeated measurements of the vessel.
Functional Analysis of the Fetal Heart
The previously discussed limited methods used to assess function of the fetal ventricles have been replaced in most studies by measurement of long axis function of the fetal heart using amplitude of displacement of the atrioventricular ring, and Doppler tissue velocities using spectral or color methods. These methods have been incorporated into routine clinical practice, whereas more research-based tools include offline assessment of strain, strain-rate, and ventricular twist and torsion.
Long Axis Function
M-Mode Measures of Displacement of the Atrioventricular Ring
The pattern of arrangement of myocytes differs in the right and left ventricles, with the right ventricle lacking myocytes aggregated in circular fashion. The myocytes aggregated in longitudinal fashion lie predominantly in the ventricular subendocardium and are affected first by ischemia. Thus reduced displacement of the atrioventricular ring may indicate early myocardial ischemia. There are additional benefits because the geometry of the right ventricle makes it difficult to assess right ventricular function in the minor axis because of poor detection of the endocardial borders. Studies in adults with heart failure have reported that assessment of the amplitude in the long axis predicts exercise tolerance and survival. Displacement of the atrioventricular ring is assessed using M-mode techniques and reflects shortening of the myocytes aggregated in longitudinal fashion toward the apex of the ventricle in systole and their active lengthening in diastole. The methodology is simple and reliable, and offline assessment using anatomic M-mode provides comparable values when fetal lie is transverse. Normal reference ranges have been described in the fetus and adult.
A comparison with postprocessing M-mode measurements of displacement derived from 3D volumes has shown good correlation. Nomograms show age-related increases in amplitude of displacement in the fetus, confirming right ventricular dominance as the right ventricular free wall shows increased displacement compared with the left or the ventricular septum.
Doppler Tissue Imaging
Doppler tissue imaging can be performed using two modalities, spectral and color Doppler imaging. Spectral imaging produces higher values than those obtained with color. Technologic differences may explain some of the reported differences in values.
Color Doppler imaging produces information from the whole imaging field and not just the tissue selected by placing a Doppler sample volume. This allows assessment of multiple sampling points in the same cardiac cycle. Furthermore, it produces velocity vectors that have the potential to be manipulated by automated programs. Spectral Doppler allows the placement of a sample volume, but the sampling usually produces a spectrum of velocities, depending on the gain settings and this can influence the peak systolic velocity measured.
Ventricular long-axis shortening velocities and amplitude correlate with overall ventricular function as assessed by ejection fraction, and early and late diastolic lengthening velocities correlate with ventricular filling velocities assessed by Doppler. Maturational changes have been characterized in the normal fetus and gestationally related values show similar increases.
Long-axis fetal cardiac function has been studied using M-mode and tissue Doppler in pregnancies complicated by maternal disease, such as diabetes mellitus and fetal growth restriction and altered function has been described.
The inconsistencies in reported results are due in part to the technical limitations in applying these measurements, developed in adult hearts, to the smaller fetal heart. There is a lack of electronic gating, and smaller tissue volumes appear to be the most important. In addition, all Doppler modalities require high frame rates, with 200 Hz being ideal (although velocities nearer to 100 Hz are more usual using ultrasound machines with obstetric platforms) and must be closely aligned parallel to the mural motion, ideally less than 20 degrees. Accuracy of measurement requires that the sample volume is small, and velocity limits reduced to optimize the trace. The technical differences in these methods and in recordings made on different equipment lead to different results, and this must be recognized as a limitation when comparing different studies or changing equipment during longitudinal studies.
Development of software is underway to permit an automated assessment of the myocardial vector traces obtained using color tissue Doppler, and this may improve performance of the technique.
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