Heart Fail Rev DOI 10.1007/s10741-017-9638-z

Fetal programming as a predictor of adult health or disease: the need to reevaluate fetal heart function Joana O. Miranda 1,2 José Carlos Areias 1,7

&

Carla Ramalho 3,4,5 & Tiago Henriques-Coelho 6,7 &

# Springer Science+Business Media, LLC 2017

Abstract Epidemiologic and experimental evidence suggests that adverse stimuli during critical periods in utero permanently alters organ structure and function and may have persistent consequences for the long-term health of the offspring. Fetal hypoxia, maternal malnutrition, or ventricular overloading are among the major adverse conditions that can compromise cardiovascular development in early life. With the heart as a central organ in fetal adaptive mechanisms, a deeper understanding of the fetal cardiovascular physiology and of the echocardiographic tools to assess both normal and stressed pregnancies would give precious information on fetal wellbeing and hopefully may help in early identification of special risk groups for cardiovascular diseases later in life. Assessment of cardiac function in the fetus represents an additional challenge when comparing to children and adults, requiring advanced training and a critical approach to properly acquire and interpret functional parameters. This review * Joana O. Miranda [email protected]

summarizes the basic fetal cardiovascular physiology and the main differences from the mature postnatal circulation, provides an overview of the particularities of echocardiographic evaluation in the fetus, and finally proposes an integrated view of in utero programming of cardiovascular diseases later in life, highlighting priorities for future clinical research. Keywords Cardiac function . Echocardiography . Fetal programming . Fetus . Fetal growth restriction

Abbreviations AV Atrioventricular ECG Electrocardiogram FGR Fetal growth restriction LV Left ventricle MPI Myocardial performance index RV Right ventricle TDI Tissue Doppler imaging TTTS Twin-to-twin transfusion syndrome 2D-ST 2D-speckle tracking

1

Department of Pediatric Cardiology, São João Hospital, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal

2

Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal

Introduction

3

Center of Prenatal Diagnosis, Department of Gynecology and Obstetrics, São João Hospital, Porto, Portugal

4

Faculty of Medicine, University of Porto, Porto, Portugal

5

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

6

Cardiovascular R&D Centre (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal

7

Department of Pediatrics, Faculty of Medicine, University of Porto, Porto, Portugal

Fetal cardiovascular physiology is uniquely different from the Btransitional circulation^ of the newborn and dramatically different from the mature circulation of the older infant and adult. Unique characteristics of the fetal myocardium, normal maturation of the cardiovascular system throughout pregnancy, and specific physiological shunts differentiate the physiology of the fetus from the newborn and the adult. It is currently recognized that adverse conditions in intrauterine life may cause a dysfunctional development of the cardiovascular system and

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program long-term adverse consequences on the cardiovascular health later in life [1]. Echocardiography has improved our understanding of human fetal cardiovascular physiology in the normal and stressed pregnancies and has expanded our capability to more effectively assess the fetal response to adverse conditions in utero. However, the assessment of fetal cardiac function is still a challenge for researchers and clinicians. This review summarizes the basic fetal cardiovascular physiology and the main differences from the mature postnatal circulation, and it provides an overview of the technical particularities and limitations of echocardiographic cardiac function evaluation and applicability in the fetus. Finally, it proposes an integrated view of in utero programming of cardiovascular diseases later in life, highlighting priorities for future clinical research.

Fetal cardiovascular physiology The primary function of the heart is to eject blood in order to provide adequate perfusion of the organs. In intrauterine life, the function of the cardiovascular system is critical for embryonic and fetal survival and growth, with the heart working as a central organ in fetal adaptive mechanisms. Embryologically, the heart begins as a primitive tube and subsequently undergoes looping, septation, valve formation, and compaction to become a fully septated four-chamber heart [2]. Cardiac morphogenesis occurs between days 20 and 44 after fertilization and myocardium undergoes a process of progressive compaction, which is intimately connected to the development of the mural coronary arterial supply. Cardiac performance is classically conditioned by four major determinants—preload, afterload, contractility, and heart rate—which affect fetal heart distinctively from adult hearts. Furthermore, myocardial maturation and blood circulatory changes occurring during gestation are also critical factors for fetal heart performance. The knowledge of this particularities is crucial for understanding of fetal cardiac function assessment and its potential limitations. Fetal myocardium Fetal myocardium differs from adult myocardium in a number of ways. First, studies in isolated myocardium and intact hearts have shown that fetal myocardium is less compliant and with low elasticity than that of the adult [3, 4]. Fetal myocardium is comprised of greater non-contractile elements and has fewer myofibrils, which are arranged in a more random orientation rather than a parallel organization which occurs in adults [5]. The normal maturation of fetal myocardium and evolving diastolic properties, with increasing number of cardiomyocytes

and declining matrix content [6], is reflected on the changes in flow velocities waveforms across atrioventricular (AV) valves. After 5 weeks of gestation, the heart rhythm is generally regular [7], and AV velocity waveforms can be recorded by echocardiography as early as 8 weeks of gestation. Mostly monophasic before 9 weeks, they become biphasic thereafter with a greater percentage of ventricular filling occurring during atrial contraction (A-wave) rather than during early ventricular filling (E-wave) [8]. Interestingly, the E/A ratio in fetal life resembles the inverted mitral inflow pattern seen in the stiffer ventricles of elderly people. The gestational agedependent rise in E/A ratio suggests a shift of blood flow from late diastole toward early diastole, which probably reflects a normal progressive myocardial maturation toward a more distensible ventricle and a more rapid ventricular relaxation later in pregnancy [8–11]. This inherent fetal Bdiastolic dysfunction^ affects the ability of myocardium to relax and adapt to stressors, reducing functional reserve of fetal heart. Second, fetal myocardium is less efficient at contraction. Differently from mature myocytes, fetal myocytes rely on trans-sarcolemmal calcium influx [12]. A poorly developed T-tubular system and an impaired sarcoplasmic reticulum vesicles calcium uptake system also contribute to differences in myocardial contraction of the fetuses [13]. Third, cell metabolism is also immature in fetal myocardium. Long-chain fatty acids are the preferred energy source in adults, while lactate is the primary agent metabolized in the immature myocardium due to a physiological deficiency in the enzyme carnitine palmitoyl transferase-1 in the fetus, responsible for transporting long-chain fatty acids into the mitochondria [14]. Fourth, prenatal growth of the heart is primarily due to cardiomyocytes proliferation. A switch from hyperplastic to hypertrophic cellular growth occurs during late prenatal or early postnatal life [15, 16], and after which, cardiac cells become increasingly differentiated and therefore lose the ability to proliferate. The net cardiomyocyte number declines continuously between young adulthood and senescence confirming the importance of cardiomyocyte proliferation in the developing heart. A reduced number of cardiomyocytes at birth may render the heart more vulnerable in situations where an increased workload is necessary. When stimulated under stress conditions, fetal cardiomyocytes can grow in size. But, interestingly, while postnatal cardiomyocytes hypertrophy is typically associated with increased production of the contractile elements, so that the enlarged cell can perform more work, that is not the case in the fetus [17]. Finally, a major factor to take into account are the dramatic changes occurring in myocardium architecture throughout p r e g n a n c y. D e s p i t e t h e n u m e r o u s s t u d i e s o n myofibrillogenesis, the interpretation of its complex arrangement remains controversial with two main conflicting viewpoints: Torrent-Guasp and colleagues advocate the concept of

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a Bunique myocardial band^ originating from the pulmonary trunk and terminating at the aorta [18], while Anderson and colleagues find no support for such organization, advocating the importance of supportive collagenous matrix and the concept of intertwined helices [19]. The process of trabecular compaction, which transforms a single-layered tube into a mature multi-layered compact zone, coincides with functional deployment of coronary circulation. This typical three-layered structure, with an innermost longitudinal, middle circular, and subepicardial oblique preferential orientation, matures during fetal development [20]. The compaction process may be affected by several conditions in utero, resulting in different distributions of fibers across the wall. Studies showed that mechanical load plays a critical role as an epigenetic factor in determining both local myofiber orientation and maturation process in the developing compact myocardium [21–24]. The development of new echocardiographic tools to assess myocardial function will likely expand our knowledge about these adaptive and/or maladaptive processes in response to stressors. Fetal circulatory system The arrangement of human circulation in utero is also very unique with the two ventricles pumping in parallel to the systemic circulation. Left ventricle (LV) ejects into the ascending aorta and head and neck vessels—a low-compliance and highresistance circulation—whereas right ventricle (RV) ejects into the descending aorta and its branches through a large ductus arteriosus—mainly a high-compliance and low-resistance circulation. Although the umbilical-placental vasculature presents a high impedance during the embryonic period, it decreases afterward with the development of a very extensive network of capillary plexuses on the second and third trimesters. The three physiological shunts—foramen ovale, ductus arteriosus and ductus venosus—are essential distributional arrangements, making fetal circulation a flexible and adaptive system for intrauterine life. Their hemodynamic properties and functional changes constitute important determinants for the development of the fetal heart and circulation during the second and third trimesters [25]. Determinants of cardiac function and particularities of fetal circulation Preload Fetal myocardium has little preload reserve [26]. In intact hearts, ventricular volume at end-diastole determines sarcomere length and the force of contraction, the basis of Frank– Starling mechanism. Although the Frank–Starling mechanism is intact in fetuses, the fetal heart is normally operating near

the top of its ventricular function curve [27]. Animal studies with fetal lambs showed that a fall in preload results in a significant decrease in ventricular output but, on the other hand, a rise in preload causes only a limited increase in output. Therefore, whereas normal adult myocardium significantly increases stroke volume with increasing preload, fetal heart reaches a plateau without further increases in stroke volume. This is mainly explained by intrinsic proprieties of the immature myocardium, by the high compliance of the umbilical– placental vasculature, which limits the preload response to volume overload, and finally by the diastolic ventricular interaction due to the similarity of pressures of both ventricles. Afterload Fetal and newborn hearts appear to have a relatively modest Bsystolic reserve,^ making the heart particularly susceptible to acute ventricular afterload. This results in a marked decrease in cardiac output for small afterload increases, in contrast to a mild increase in cardiac output with afterload reduction [28]. A number of pregnancy complications or congenital heart diseases can affect loading conditions to each ventricle. The paradigm of fetal RV afterload increasing is ductus arteriosus constriction, for example, due to maternal use of nonsteroidal anti-inflammatory agents. Animal experimental studies showed that a mechanically induced ductal occlusion results in a significant decrease in RV output associated with just a moderate increase in LV output, together with signs of LV diastolic dysfunction, resulting in a significant reduction in combined cardiac output [29, 30]. Other fetal conditions that increase RV afterload, like severe placental insufficiency, may also cause a shift in fetal cardiac output from RV to LV with impact on cardiac function [31]. A high afterload also imposes modifications in the cardiomyocytes and remodeling of the walls of the heart and major vessels, which seem to persist later in life [32, 33]. Contractility Animal studies of isolated myocardium have demonstrated that fetal myocardium develops less active tension than adult myocardium at similar muscle lengths, resulting in lower contraction velocity and lower maximal contractile force [4, 27, 34]. The causes for this difference are many and discussed above: few functioning myofibrils, structural and functional immaturity of the sarcoplasmic reticulum, but also reduced ßadrenergic receptor density and the expression of less efficient fetal contractile proteins isoforms. More recent studies in human myocytes suggest that myofibril force production and rates of activation and relaxation increase significantly as gestation progresses. These factors are influenced by the structural maturation of the sarcomeres and changes in contractile filament protein isoforms [35].

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Heart rate The development of fetal heart rate over the course of gestation is the product of neural and nonneural influences that undergo several changes during development [36]. In normal pregnancy, the fetal heart rate increases from about 110/min at 5 weeks of gestation to 170/min at 9 weeks and then gradually decreases to about 150/min by 14 weeks as result of functional maturation of the parasympathetic system [37, 38]. Whereas in adults the cardiac output is relatively stable over a wide range of heart rates, in fetuses, increased heart rate may be the single most prominent mean of increasing cardiac output [25]. In studies with fetal sheep, spontaneous increases in heart rate above the resting level of about 160/min are associated with increases of ventricular output of up to 15– 20%, and spontaneous decreases in heart rate result in a significant fall in output [27]. This may be due to a direct positive effect of heart rate on ventricular output or due to the concomitant effects of the inotropic stimuli. Fetal heart rate can be used as a marker for fetal well-being. It is highly sensitive to hypoxia and, unlike the adult circulation, the fetal heart responds with bradycardia due to activation of a chemoreflex mediated by the carotid bodies and to a lesser extent the aortic bodies [39–41]. Other reasons for alterations in fetal heart rate include changes in placental blood flow, external stimuli, increases in temperature, or drugs. Fetal heart rate is the earliest functional parameter that can be measured in intrauterine life. In the embryonic period bradycardia is associated with a poor prognosis for the pregnancy [42, 43].

hamper proper acquisition of certain views and assessment of parameters critically affected by the angle of insonation. These limitations, together with the particularities of fetal cardiovascular physiology, warrant advanced training and a critical approach to properly acquire and interpret functional fetal echocardiography. In this section, we will review the main techniques and indices of fetal cardiac function and its limitations (Table 1). Cardiac morphometry Measurement of valves and chambers dimensions is an important part of fetal heart assessment. M-mode and B-mode can be used. M-mode has a better temporal resolution but requires the heart to be in a specific orientation for accurate measurements. B-mode allows the examiner to measure multiple cardiac structures, irrespective of orientation to the ultrasound beam. Normal data and z scores for chambers and valves dimensions can be found in the literature for different assessment methods [46]. Cardiothoracic ratio can be used to quantitatively express the degree of cardiac enlargement. It is calculated by measuring the fetal cardiac and thoracic areas or circumferences, in axial section, and is considered normal below 33 and 50%, respectively. Overall cardiac size is often a sign of altered hemodynamics in fetus, as cardiomegaly can be seen in different sets of heart failure [47]. Systolic function Ejection fraction and shortening fraction

Main techniques and indices to assess fetal cardiac function Over the years, many parameters have been proposed to quantitatively evaluate cardiac function. Most were first developed for adult patients and then adapted to fetus. Different ultrasound imaging modalities—M-mode, B-mode, and conventional Doppler—have traditionally been used to assess cardiac morphometry, blood flow velocities, cardiac output, and timing of cardiac cycle events. More recently, tissue Doppler imaging (TDI) and 2D-speckle tracking (2D-ST) are being used in fetuses for evaluation of global and regional myocardial motion and deformation. 4D spatiotemporal image correlation has also been proposed to more accurately evaluate cardiac dimensions and volumes and to estimate cardiac output and ejection fraction [44, 45]. Assessment of cardiac function in fetal heart represents an additional challenge when comparing to children and adults, because of its small size and high heart rates, restricted physical access to the fetus, and impossibility of fetal electrocardiogram (ECG) recording. Fetal lie and movements may

Ejection fraction and shortening fraction can be computed from end-diastolic and end-systolic dimensions of LV and RV measured by M-mode [46, 48] (Table 1). It requires a perpendicular view to the interventricular septum at the level of the AV valve leaflets, which can be difficult to obtain in fetuses. They are late systolic dysfunction markers, as they appear to be affected only in very late stages of fetal diseases since it mainly reflects radial function [49]. Cardiac output Stroke volume for both ventricles, and therefore cardiac output, can be calculated by combining B-mode to measure the diameter of the semilunar valve and pulsed-wave Doppler to measure the velocity time integral of flow across the valve [46] (Table 1). Small inaccuracies measuring valvar diameters, as the square of this value is used, or deviation on the insonation angle of pulsed-wave Doppler >15–20° result in major imprecisions of cardiac output calculation. Combined cardiac output is expressed as the sum of LV and RV cardiac outputs and is typically indexed to the estimated fetal weight.

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Summary of most commonly used fetal cardiac function indices

Parameters

Imaging modality

Definition/formulas

Morphometry Valvar and chamber dimensions Cardiothoracic ratio Systolic function Ejection fraction Shortening fraction

2D, MM, STIC 2D

Cardiac area or circumference divided by thoracic area or circumference, on 4-chamber view in axial section

2D, MM, 2D-ST, STIC

Fraction of blood ejected from the ventricle with each heart beat; Ejection fraction = (ED volume − ES volume)/ED volume

2D, MM, 2D-ST, STIC

Cardiac output

Percent change in ventricle cavity dimensions at the base with systolic contraction; shortening fraction = (ED dimension − ES dimension)/ED dimension 2D, PWD, STIC Volume of blood ejected by the ventricle per minute; cardiac output = SV * HR; SV = (π * D2) /4 * VTI

Annular displacement

MM

Maximal displacement of the valve annulus between diastole and systole

Systolic annular peak velocity Strain

TDI

Speed of movement of AV valve annulus in systole (S′)

2D-ST, TDI

Amount of deformation (change in length of a myocardial segment from its original length)

Strain rate Diastolic function E/A ratio

2D ST, TDI

Speed of deformation (change of strain over time)

PWD

Ratio between early (E) and late (A) ventricular filling velocity

Isovolumic relaxation PWD, TDI time Diastolic annular peak TDI velocities Diastolic deformation 2D-ST Global cardiac function

Time between aortic valve closure and mitral valve opening

Myocardial PWD, TDI performance index Fetal vascular flow pattern

Ratio between isovolumic times (contraction + relaxation) and ejection time

Venous duct Umbilical artery

PWD PWD

Flow waveform analysis (absent or reversal A-wave); S/A wave ratio; PI = (PSV − PDV)/TAMV Flow waveform analysis (absent or reversal A-wave; continuous versus pulsatile blood flow); PI

Middle cerebral artery

PWD

Flow waveform analysis (increased end-diastolic flow velocity); PI; PSV

Speed of movement of the AV valve annulus in early (E′) and late (A′) diastole Amount of deformation (change in length of a myocardial segment from its original length)

2D 2-dimensional, 2D-ST 2-dimensional speckle tracking, AV atrioventricular, D valve diameter, ED end-diastolic, ES end-systolic, HR heart rate, MM M-mode, PI pulsatility index, PSV peak systolic velocity, PDV peak diastolic velocity, PWD pulsed-wave Doppler, SV stroke volume, STIC spatiotemporal image correlation, TAMV time averaged maximum velocity, TDI tissue Doppler imaging, VTI velocity time integral

There are published normal values available for indexed combined cardiac output in the fetus, which range from 225 to 625 ml/min/kg [50]. The cardiac output increases as a function of gestational age, as both the diameters of semilunar valves and the flow velocities through the outflow tracts increase in a linear fashion with advancing gestation. As for the ejection fraction, cardiac output only becomes abnormal in late stages of cardiac function deterioration [51, 52]. Therefore, more sensitive parameters have been proposed for earlier diagnosis and monitoring of fetal cardiac dysfunction. Myocardial motion and deformation The former parameters of systolic function represent global ventricular ejection and thus the result of overall ventricular deformation. As said, changes in theses parameters reflect late events in fetal heart dysfunction. Quantifying regional motion and deformation allow to assess different components of deformation

individually and they are thought to represent earlier manifestations of subclinical cardiac dysfunction [53]. Annular displacement is a sensitive ventricular dysfunction marker as it is mainly determined by subendocardial fibers contraction, which are the ones farthest from the epicardial blood supply and consequently with lower supply under milder degrees of hypoxia [54]. The M-mode cursor is placed over the AV valve parallel to its excursion, and maximal displacement of the valve ring between diastole and systole is recorded (Fig. 1a). For both fetus and adults, this method is most suited for RV examination considering the longitudinal orientation of the deep RV muscle fibers, as opposed to the mainly circumferential arrangement of LV muscle fibers. The RV measurement is often referred to as TAPSE (tricuspid annular plane systolic excursion). Similar to the other systolic function markers, a linear increase in valve annulus displacement throughout gestation is observed for both AV valves during fetal life [55].

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Fig. 1 a Right ventricle (RV) annular displacement using M-mode. Interrogation line placed through the ventricular free wall attachment of the tricuspid valve. The difference of maximal systolic and diastolic excursion is measured. b Tissue Doppler imaging. Pulsed-wave tissue Doppler interrogation of RV: S′- systolic downwards motion of myocardium toward the apex, E′ early diastolic movement, A′ atrial contraction movement. c Left ventricle (LV) deformation study using 2D speckle tracking. Top left: LV tracking of endocardial and epicardial

borders in a four-chamber view; top right: six individual LV segment strain curves displayed as a function of time; bottom right: table record showing peak strain values for each segments. d LV myocardial performance index using pulsed-wave Doppler. Doppler waveform displays the opening and closing clicks of the mitral and aortic valves: ICT—from the closure of the mitral valve to the opening of the aortic valve; ET—from the opening to the closure of the aortic valve; IRT— from the closure of the aortic valve to the opening of the mitral valve

While in the past segmental deformation could only be evaluated experimentally by invasive techniques like sonomicrometry, currently TDI and 2D-ST image-based techniques offer the possibility to quantify deformation under more physiological conditions, as well as to investigate patients in the clinical setting. Although not currently part of the routine fetal echocardiogram, they are promising tools for the functional cardiac evaluation in special conditions. Deformation imaging, in the broadest sense, allows for more direct assessment of myocardial muscle shortening and lengthening throughout the cardiac cycle by assessing regional myocardial strain and strain rate. Strain is defined as the change in length of a myocardial segment relative to its resting length and is expressed as a percentage, and strain rate is the rate of deformation. Longitudinal and circumferential shortening results in negative strain values, whereas thickening results in positive strain values [56].

Initially developed for adult patients, TDI is used in this group for early identification of subtle cardiac dysfunction in preclinical stages and as a prognostic tool in major cardiac diseases [57, 58]. First reported as feasible for fetal myocardium in 1999 [59], was then explored by different research groups and consolidated as a reproducible echocardiographic technique. By eliminating the wall filter and using low-gain amplification, myocardial tissue velocities can be displayed by TDI using the pulsed-wave Doppler technique, twodimensional color-Doppler map, and color-M-mode image. Online analysis of peak velocities evaluated at the mitral or tricuspid annulus reflect global myocardial motion in systole (S′, a positive deflection waveform) and diastole (E′ and A′, negative deflection waveforms) (Fig. 1b). Offline analysis using color-TDI allow for calculation of strain and strain rate. TDI should be used with caution in fetal hearts since it has several limitations compared with its use in adults, concerning to fetal lie and fetal movements, critical need for a high frame

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rates more difficult to obtain in utero, absence of coregistration with ECG, and limited resolution of ultrasound machines [60]. Normal fetal values have been reported for both pulsed-wave and color-encoded techniques [55, 61, 62]. Off notice, initial studies were based on acquisitions with very low temporal resolution (10–60 fps), which strongly limited the validity of the findings. Lately, studies using high frame rate acquisitions showed good feasibility ranging and high agreement for TDI-derived velocities and time intervals [63, 64]. Speckle tracking is a more recent tool based on the tracking of unique speckle patterns or Bkernels^ in the myocardium throughout the cardiac cycle. In contrast to TDI, 2D-ST is a non-Doppler technology based on offline 2D image analysis that tracks the moving image, frame by frame, to allow assessment of myocardial deformation along all the threedimensional geometrical axes (longitudinal, circumferential and radial) [63, 65, 66]. It computes multiple derivative parameters, including myocardial strain, strain rate, and velocity (Fig. 1c). Longitudinal strain, in particular, has proven to have a high sensitivity and reliability in adult hearts, probably because it is a marker of the subendocardial function early involved in many pathological processes. The parameter called systolic Bglobal longitudinal strain^ has gained increasing interest in adults and is currently being used as a diagnostic and prognostic indicator or as an alternative to LVejection fraction [66]. In fetuses, the feasibility of myocardial speckle tracking has already been reported [65, 67–70]. The analysis is based on standard gray-scale images of the four-chamber view, which are routinely obtained in fetal echocardiography. Major attractions of this technique for fetal heart are its lack of angle dependence, ease of acquisition, rapid post-processing, and the ability to assess both systolic and diastolic deformation. Recent studies, using high frame rates and dummy ECG based on mitral valve motion, showed that deformation can be assessed in a reproducible way when using the appropriate methodology [67–70]. 2D-ST has the potential to provide new insights into the understanding of fetal heart function in specific disease states. Little is currently known about how different stages of ventricle compaction in the normal developing heart influence the different deformational components and whether fetal adverse conditions, that clearly affect compaction process, have consequences for deformation and cardiac function from fetus to adults.

reversed fetal E/A ratio has been described in fetal disease states [71–73]. Monophasic atrioventricular inflow patterns after 9 weeks’ gestation are seen at high fetal heart rates and also in fetuses with cardiac function deterioration [47]. Isovolumic relaxation time Isovolumic relaxation time (IRT) is the interval between closure of the semilunar valves and opening of the AV valves [74]. It is usually used as part of myocardial performance index (MPI) discussed below. This period reflects the process of calcium reuptake, which can be reduced in a deteriorated cardiac function. It is relatively stable throughout gestation and becomes prolonged in the very early stages of diastolic dysfunction, such as in early-onset fetal growth restriction (FGR) or gestational diabetes [51, 71]. Diastolic annular peak velocities by TDI TDI can directly measure myocardial relaxation velocity [55, 60–62]. It has been observed that diastolic function assessed by TDI, unlike conventional pulsed-wave Doppler, appears to be less influenced by loading conditions. Data on fetal diastolic function showed that as gestation advances ventricular relaxation becomes increasingly mature and the E′/A′ ratio reaches unity at term [55, 62]. The E/E′ ratio (between early mitral inflow velocity and mitral annular early diastolic velocity) is a valuable diastolic indicator in adults as it correlates with ventricular filling pressure [75]. However, its value in fetal echocardiography is still incompletely understood. Diastolic deformation by 2D-ST The study of diastolic deformation is an incipient work in fetal cardiology. Abnormal myocardial deformation has been reported in various forms of cardiac and extracardiac fetal pathologies; however, diastolic deformation, specifically, has rarely been studied. A few studies suggest that abnormal diastolic strain and strain rate values may be related to diastolic dysfunction [70], but the clinical significance of diastolic strain needs further studies. Global cardiac function MPI

Diastolic function E/A ratio The ventricular filling pattern reflects relaxation properties of the ventricles. In healthy fetuses, as discussed previously, Awave is greater than the E-wave and E/A ratio increases progressively with advancing gestation [9]. An increased or even

Myocardial performance index or BTei^ index is considered a marker of global cardiac function, as it comprises both systolic and diastolic components. It was first reported in adults in 1995 [76] and applied to fetus years later, in 1999, by Tsutsumi and colleagues [74]. It is obtained by echocardiographic evaluation of the flow patterns through AV valves and outflow tracts, usually obtained with pulsed-wave Doppler,

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but can also be obtained using M-mode and TDI (Fig. 1d). Its calculation is the sum of the isovolumic contraction (ICT) and relaxation (IRT) times, divided by the ejection time (ET) (Table 1). MPI measured in fetuses has advantages over its application in adults. Friedman and colleagues [77] showed that all components of left MPI could be measured in the same waveform, as the aortic and mitral valves are located closer and can be assessed in the same Doppler sample gate, thereby removing the inaccuracy involved in measuring the time intervals across different heart beats. The right-sided valves cannot be captured simultaneously due to their different anatomical configuration. Different authors have proposed different positions of the time cursor for estimation of time intervals: the beginning of valve clicks (original modification of MPI) [78], end of valve click (as physiological representation of the valve movement) [79], and the peak of valve clicks (as a clearer landmark and to overcome the width of the valve click) [80]. Thus, for an accurate measurement and to look for normal reference values, technical aspects must be judiciously considered. MPI has been widely studied in a number of fetal pathologies, including FGR [51], twin-to-twin transfusion syndrome (TTTS) [71], constriction of the ductus arteriosus [81], and cardiomyopathy, and was shown to be significantly elevated, mainly due to a prolongation of IRT. It has been proven to be a sensitive parameter of cardiac dysfunction and may represent initial stages of cardiac adaptation to different perinatal insults.

Fetal vascular flow pattern Fetal Doppler ultrasound provides a non-invasive method for studying fetal hemodynamics. Doppler waveforms of the precordial veins mirror volume-pressure changes in the right atria throughout cardiac cycle [11]. Particularly ductus venosus Doppler can add valuable information to comprehensive fetal echocardiogram. The typical waveform for blood flow in venosus vessels consists of three phases: ventricular systolic phase (S-wave), early diastolic phase (D-wave), and late diastolic phase (A-wave) [82, 83]. The most significant change of ductus venosus in cardiac dysfunction is the absence or reversal of flow during atrial contraction (A-wave), which may reflect myocardial impairment and increased ventricular enddiastolic pressure. It represents a poor prognostic sign with subsequent risk of worsening fetal well-being and intrauterine death [84]. Ductus venosus flow assessment is currently an integral part of the 11- to 13-week scan because extensive studies have demonstrated that abnormal flow in this vessel is associated with an increased risk for chromosomal abnormalities, cardiac defects, and other adverse pregnancy outcomes both in singletons and twin pregnancies [83, 85, 86].

Umbilical artery Doppler evaluates the resistance of blood perfusion of the fetoplacental unit. As early as 14 weeks, a low impedance in the umbilical artery allows continuous flow throughout the cardiac cycle. Absent or reversed enddiastolic flow in the umbilical artery occurs in placental insufficiency and represents an increased placental vascular resistance and enhanced RVafterload. An elevated umbilical artery pulsatility index, a direct sing of a high impedance to blood flow in the placenta, is one of the earliest vascular Doppler signs to become abnormal in FGR [87]. Middle cerebral artery Doppler, under normal conditions, shows a high impedance circulation with continuous forward flow throughout the cardiac cycle. In situations of fetal hypoxia, there is a central redistribution of blood flow with increased blood flow to the brain, heart, and adrenal glands and reduced flow to the peripheral circulations. This blood flow redistribution, known as Bbrain-sparing effect,^ is characterized by increased end-diastolic flow velocity in the middle cerebral artery (reflected by a low pulsatility index) [87]. It results in a decrease of LV afterload. Cerebroplacental ratio, calculated by dividing pulsatility index of middle cerebral artery by umbilical artery, is an important obstetric tool. It has been demonstrated to be more sensitive to hypoxia than its individual components and correlates better with adverse outcome [87]. New technologies In the last years, the new technology 4D spatiotemporal image correlation (STIC) has been proposed to quantify ventricular volumes, cardiac output, and ejection fraction in fetal hearts, presumably allowing for a more accurate estimation than twodimensional modalities [44]. STIC consists in an automated volume acquisition technology that allows information to be stored in 4D cine loop sequences [88]. Within volume data sets, a specific cardiac phase (end-diastole or end-systole) can be identified by observing the opening and closing of the AV and semilunar valves. Afterward, by capturing these time points within the cardiac cycle, ventricular volume measurements may be obtained. STIC is a promising technique, still in its early stages, and more research work is required before it can be spread to clinical practice. Fetal heart team Given the spectrum and complexity of cardiac pathology in fetal life and the expansion of the tools available for a detailed anatomical and functional assessment of the fetal heart, the definition of the team responsible for the fetal echocardiographic assessment remains controversial. A second trimester obstetrical ultrasound screening, incorporating multiple views of the heart, has become the mainstay of screening for fetal heart diseases [89]. A fetal echocardiogram should be

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performed when there is a suspicion of a cardiac disease on routine obstetric ultrasound or when there are recognized risk factors for increased risk for congenital heart disease [89, 90]. Current guidelines recommend that the fetal echocardiography should be performed and interpreted by personnel who have had formal training or experience in fetal echocardiography and exhibit continuing education in and experience with the diagnosis of congenital heart disease [89]. Specific guidelines for training for physicians entitle to perform these examinations were developed by different scientific organizations [89, 90]. First trimester cardiac evaluation is becoming more common in the last decade [91]. Recent studies showed that first trimester screening have a significant impact on the spectrum of congenital heart diseases and the outcomes of pregnancies with congenital heart diseases diagnosed in the second trimester [91, 92]. Challenges of this method include limitations in image resolution with potential to miss more subtle lesions, the potential for the progression of lesions undetectable at earlier gestation, and the need for highly trained and experienced examiners. Therefore, repeat mid-trimester assessment of all pregnancies evaluated before 15 to 16 weeks is recommended [89].

Cardiovascular assessment in fetal conditions Fetal response to stress Various fetal conditions can compromise cardiovascular status and fetal well-being, such as FGR, TTTS, or maternal diabetes, due to a combination of hypoxic insult, pressure or volume overload, or malnutrition (Table 2). Besides the hemodynamic adaptation, factors in the intrauterine environment resulting from both normal and stressed pregnancies act directly on developing heart to modulate cardiomyocytes hyperplasia and hypertrophy [6], which may impact on prenatal and postnatal cardiac function. With the heart as a central organ in fetal adaptive mechanisms, cardiovascular assessment during pregnancy can give precious information on fetal well-being and hopefully may help in early identification of special risk groups for cardiovascular diseases later in life. Fetal hypoxia Fetal hypoxia is a major deleterious factor in various prenatal conditions, including placental insufficiency in FGR, fetal anemia, maternal smoking, or inflammatory conditions such as chorioamnionitis. Although fetal hearts show remarkable ability to survive and function under low oxygen tension, chronic abnormal hypoxia alters myocardial development and coronary vessel growth and may cause a decline in cardiac performance [119]. Animal studies suggest that hypoxia has a direct inhibitory effect on cardiomyocyte proliferation in the

developing heart [120] and also results in a fetal blood redistribution, the so-called brain-sparing effect. While vasodilation in the cerebral vascular bed during hypoxia occurs mainly as a result of a local increase of adenosine, peripheral vasoconstriction and consequent increment of peripheral vascular resistance is triggered by a carotid body chemoreflex [121]. In human growth-restricted fetuses, chronic fetal hypoxia is associated with echocardiographic signs of cardiac function impairment. Overt signs of systolic dysfunction are rare and appear only in severely affected fetuses, but more subtle signs of dysfunction have been demonstrated based on recent myocardial imaging techniques of decreased systolic and diastolic annular peak velocities [53, 93], as well as impaired ventricular relaxation showed by higher E/A ratios [51, 72, 73] or increased IRT [51]. Maternal malnutrition Maternal nutritional status, both nutrient deprivation or excess, have a great impact on fetal cardiovascular development and function. Maternal undernutrition during different stages of pregnancy can induce diverse significant changes in the structure, physiology, and metabolism of the offspring depending on the timing of the insult. What we know from animal studies is that maternal undernutrition from early- to mid-gestation leads to growth retardation and cardiac ventricular hypertrophy in late gestation [122]. This compensatory growth seems to be at least in part related with upregulation of cardiac insulin-like growth factor (IGF) receptors [123] and associated with increased transcription of genes related to cardiac compensatory hypertrophy or remodeling [124]. In contrast, in late gestation, a reduced maternal body composition and lower circulating blood glucose concentrations are associated with an elevated blood pressure and greater vasoconstrictor activity [125], which may affect ventricular afterload and thereby influence myocardial development. In human fetuses, maternal undernutrition is mostly assessed together with FGR studies. The impact of maternal overnutrition has been less investigated than undernutrition, but the alarming rise in the prevalence of obesity in women of reproductive age and also in gestational diabetes worldwide warrants increased research efforts. It is well-known that infants of diabetic mothers are at higher risk of developing structural heart defects [126] and, more commonly, fetal hypertrophic cardiomyopathy [108]. Fetal hypertrophic cardiomyopathy is characterized by an asymmetric myocardial hypertrophy affecting mainly the interventricular septum. It can be associated with increased shortening fraction and systolic longitudinal motion [127] and signs of diastolic dysfunction, as measured by a lower E/A ratio, increased IRT, and increased annular peak velocities [71]. As changes in cardiac function become apparent before echocardiographic evidence of cardiac hypertrophy,

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Main characteristics of adverse intrauterine condition in fetal cardiovascular system and later in life

Intrauterine condition

Main pathophysiological features

Abnormal fetal echocardiogram findings

– Constant or increased E/A ratio [51, 72, 73] – Increased MPI and IRT [51] – Reduced annular longitudinal motion [53, 93] – Decreased systolic and diastolic peak velocities on TDI [53, 93] – No changes on LV peak strain and SR; postsystolic shortening on myocardial deformation imaging [94] – Absent or reversed A-wave on DV, increased diastolic flow on MCA and decreased end-diastolic flow on UA [72, 73, 87] Maternal – Proportional or accelerated cardiac growth – LV and RV hypertrophy [104] – No changes on systolic function obesity relative to somatic growth – Increased MPI and IRT – Placental vascular insufficiency – Upregulation of myocardial proinflammatory – Increased E/E′ ratio [105] mediators – Reduced LV and RV strain and SR – Myocardial fibrosis [104] – Hypertrophic cardiomyopathy Maternal – Exposure to maternal hyperglycemia pattern (thickening of diabetes – Hypoxia and oxidative stress inducing interventricular septum) [108] apoptosis – Increased peak velocities at outflow – Reduced nephron number tract – Activation of RAS – Altered angiogenesis and early endothelial – Increased shortening fraction – Reduced E/A ratio (mainly RV) dysfunction – Increased IRT – Ventricular hypertrophy – Increased peak annular velocities [71] – Reduced global longitudinal strain [109] Cardiovascular dysfunction mainly in Twin-to-twin – Unbalance volume exchange from donor the recipient twin: twin to recipient twin. transfusion – Cardiomegaly and hypertrophy syndrome – Recipient twin: hypertrophic cardiomyopathy; increased preload due to – AV valve regurgitation – Increased MPI [112] chronic hypervolemia and increased – Reduced LV and RV systolic strain afterload due vasoconstrictive agents and SR transferred from the donor – Reduced LV and RV diastolic strain – Donor twin: increased RV afterload due to [113, 114] increased placental vascular resistance and activation of RAS; reduced LV preload and – RVOTO abnormalities (ex: PS) afterload through reduction of – Absent or reversed A-wave on DV cerebrovascular resistance Donor twin: – Increased LV systolic strain and SR and decreased LV diastolic SR [113] – Reduced RV strain and SR – Increased UA pulsatility index and absent or reversed end-diastolic flow [112] Signs of cardiac dysfunction regress in the majority of fetuses following successful therapy by laser ablation Fetal growth restriction

– Chronic hypoxia + volume and pressure overload – Inhibition of cardiomyocytes proliferation – Reduced nephron number – Activation of RAS – Activation of carotid chemoreflex – Brain-sparing effect and asymmetric fetal growth

Cardiovascular morbidities later in life – In childhood, changes in cardiac shape, subclinical cardiac dysfunction, and endothelial dysfunction [32, 95–99] – In adulthood, hypertension, impaired glucose tolerance, insulin resistance, obesity, and coronary artery disease [1, 100–103]

– Hypertension, type 2 diabetes, dyslipidemia, heart disease, and premature death [106, 107]

– Obesity in children and adults [110] – Increased risk of type 2 diabetes and higher arterial blood pressure in adolescents and adults [110, 111]

– Within-twin-pair differences in LV rotation and diastolic function in monochorionic twins treated by serial aminoreduction (not observed in twins treated by laser photocoagulation) [115, 116] – Increased arterial stiffness in donor twin, if aminoreduction treatment and in recipient twin if laser photocoagulation [117, 118]

AV atrioventricular, DV duct venosus, IR isovolumic relaxation time, LV left ventricle, MCA middle cerebral artery, MPI myocardial performing index, PS pulmonary stenosis, RAS renin-angiotensin system, RV right ventricle, RVOTO right ventricular outflow tract obstruction, SR strain rate, TDI tissue Doppler imaging, UA umbilical artery

functional parameters have been suggested as useful early predictors of outcomes in these pregnancies, but their clinical

utility remains to be confirmed. They may be helpful to predict the func tion al impa ct of fetal hype rtro phic

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cardiomyopathy after birth and to distinguish between the newborns that will be clinically asymptomatic from the ones that will present potentially fatal congestive heart failure. Little is known about the pathological mechanisms underlying fetal response to hyperglycemia and its consequences for future cardiovascular health. Sheep overnutrition models showed that heart growth is proportional or accelerated relative to somatic growth [128, 129]. Cardiac hypertrophy and contractile dysfunction occur in offspring of mice with maternal obesity and diabetes likely via lipotoxicity, glucose intolerance and mitochondrial dysfunction [130]. As obesity is considered a physiological state of chronic low-grade inflammation, it is not surprising that fetal ventricular tissue shows high levels of inflammatory cytokines and inflammatory cell infiltration [131]. Loading conditions The fetal heart is particularly responsive to alterations in the hemodynamic loading, which increases during the normal gestation and can be exacerbated in pathological situations. Due to its plasticity, the developing myocardium has the ability to adjust to hemodynamic load, with modifications on the cardiomyocyte size, number, and maturation [17, 132]. An increase in afterload requires compensatory growth of the myocardial wall. According to Laplace’s law increases in intraluminal pressure will produce increased wall stress for a given radius, which is compensated by increased wall thickness or decrease internal radius [119]. Fetal sheep studies showed that experimental increasing in afterload conducts to a compensatory growth of both ventricles. But an excessive afterload can lead to dilatation of the ventricles and poor cardiac function and fetal hydrops [6]. It is less clear, however, how the increased afterload affects cardiac function and muscle deformation in the human fetus.

Fig. 2 The developmental programming hypothesis

Volume overload, typically seen in fetal anemia, valve leakage, or TTTS, causes an adaptive mechanism, where the increased end-diastolic volume causes increased stroke volume, according to the Frank–Starling mechanism. But, as discussed previously, fetal myocardium responds to preload with reduced contractile reserve. When exposed to a high preload, the ventricle remodels to cope. Initially, there is cardiomegaly and hypertrophy, and a maintained or slightly increased strain. At latter stages, chronic and progressive heart dilatation causes an increasing wall stress and tissue damage, which can lead to ventricular failure and fetal hydrops. At this stage, deformation is reduced [133]. In fetal circulation, different loading conditions to each ventricle explain ventricular-specific changes in myocardial tissue deformation. In TTTS, the donor shows an increase in LV and a decrease in RV strain and strain rate, while global depression is seen in the recipient. Cardiac dysfunction seen in the recipient results not only from volume overload but also from raised afterload due to an increase in systemic vascular resistance and pressure [112, 113] (Table 2). Fetal programming of cardiovascular diseases Epidemiological evidence has long suggested a link between adverse early life conditions and increased cardiovascular diseases in adulthood [1, 100–103]. Most notably, epidemiological studies by Barker and colleagues were the first to correlate undernutrition and low birth weight (as a proxy for fetal growth) with an increased incidence of coronary heart disease in adulthood [1, 102, 103]. The developmental programming hypothesis proposes that adverse stimuli during critical periods in utero not only distress organs development and function during fetal life but also permanently alter tissue structure and function, which may have persistent consequences for the long-term health of the offspring [102, 103] (Fig. 2). The mechanisms responsible for the

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programming of adult cardiovascular disease are still poorly understood. FGR is one of the most studied adverse fetal conditions and a major cause of perinatal mortality and severe morbidity [134]. Despite the well-established association with premature endothelial dysfunction, early progression to atherosclerosis, and cardiac structural changes in adulthood [32, 95, 96], the underlying pathogenic process is not well understood. Under chronic oxygen and nutrients deprivation, the growthrestricted fetuses may display circulatory changes, which are in part adaptations to the intrauterine environment. These adaptations, whose main aim is to preserve oxygen and nutrients supply to the key organs—brain, heart, and adrenals—might result in a dysfunctional development of the cardiovascular system and to Bprogram^ the fetus for cardiovascular morbidity later in life. The Bthrifty phenotype hypothesis,^ a constellation of metabolic and hormonal adaptations to intrauterine nutrient deprivation, was the initial most explored link between adult diseases and FGR. Currently, the existence of a direct cardiac programming and permanent cardiac remodeling as a consequence of adverse intrauterine exposure is starting to be questioned. There is growing evidence that cardiac changes in response to hypoxia and undernutrition may begin in prenatal life and persist as a lifelong feature in infancy and adulthood. This represents a new mechanistic pathway for the association between fetal growth and cardiovascular disease. It has been documented, already in childhood, that individuals with FGR show cardiac morphology changes, subclinical cardiac longitudinal dysfunction, and arterial remodeling, as well as an impaired endothelial function and a trend toward increased carotid stiffness [95, 97–99]. At the molecular level, the adaptive mechanisms occurring in FGR are a great example of epigenetic regulation of gene activity and expression. A reduction in cardiomyocyte number through either reduced cellular proliferation or increased apoptosis appears to be a central feature in FGR. The underlying events are still poorly understood but animal studies showed that they are at least in part related to suppressed levels of insulin-like growth factor 1 (IGF-1) [135–137], downregulation of cell cycle regulatory genes, and/or concomitant increase in apoptotic inducers [135]. Human studies showed that genomic imprinting is a phenomenon that plays an important role in fetal and placental development, establishing a relationship between imprinted gene expression and FGR [138]. Considering that postnatal growth of the heart is almost entirely reliant on cardiomyocytes hypertrophy and that damage to heart muscle in adulthood is typically not reparable by cell replacement, the pool of cardiomyocytes present at birth may be determinant for heart resilience or vulnerability to disease. If the total myocyte number is reduced, the

burden of increased afterload results in myocyte enlargement and hypertrophy of the ventricular wall as a compensatory mechanism to normalize wall stress [139]. Ventricular hypertrophy in children and adults is a known independent predictor of cardiovascular mortality [140]. Another factor involved is the upregulation of reninangiotensin system seen in FGR [141]. The reninangiotensin system is essential for the maintenance of normal fetal systemic arterial pressure [6, 142] and its effect on cardiomyocyte growth is complex. Plasma renin activity and circulating angiotensin-II levels are both increased in hypoxia and fetal stress and have been involved in the development of hypertension associated with FGR. The primary effect of renin-angiotensin system on cardiomyocyte growth is likely mediated by this rising of the systemic arterial pressure load and myocyte hypertrophy response to sustained loading conditions. The direct effect of angiotensin-II in cardiomyocyte hyperplasia or hypertrophy is controversial and discordant between different experimental settings. Cardiac muscle energetics is also influenced by undernutrition in utero as dysfunctional cardiac muscle energetics in adult mice offspring, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate, and decreased proton leak respiration has been described [143]. These findings taken together indicate that FGR induces global gene expression changes in the heart which act in concert to reduce cardiomyocyte number at birth and impair cardiac energy metabolism and resilience, increasing cardiovascular vulnerability to diseases later in life. More detailed studies in growth-restricted fetuses are of paramount importance to provide new insights into the mechanisms responsible for the programming of adult cardiovascular disease. Although many of the first studies have focused on restriction of fetal growth and consequent low birth weight, a wide variety of endogenous and exogenous fetal insults is now recognized to influence cardiovascular development in offspring (Table 2). The effect of TTTS, maternal diabetes, fetal anemia, or twin anemia-polycythemia sequence on cardiovascular function later in life, for example, requires further investigation, probably incorporating the recently proposed techniques for evaluation of cardiac function. It is thus of great clinical importance a deeper understanding of the mechanisms underlying pathophysiological response to adverse exposure in utero and the definition of echocardiographic markers of fetal compromise and long-term cardiovascular outcome. Prenatal identification of high-risk populations may open new opportunities for proper monitoring and early interventions in cardiovascular risk factors, improving the cardiovascular health of future generations. This concept of Bfetal programming^ provides, therefore, a unique and powerful opportunity for prevention of cardiovascular diseases in the growing child and adulthood.

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Conclusions The fetal programming hypothesis indicates that abnormal influences during pregnancy can alter organs structure and function, which may have implications later in life. Thus, it creates an exciting window of opportunity to diagnose and prevent the development of heart diseases at its very origin. However, the mechanisms underlying the programming of cardiovascular diseases remain largely unknown. A deeper understanding of the fetal cardiovascular physiology and the utility of fetal echocardiographic tools, in both normal and stressed conditions, would help to more effectively establish markers of fetal cardiac dysfunction. It is necessary to understand the fetus as a patient knowing that cardiac function plays an important role in fetal wellness and it is a potential key link between fetal life and future cardiovascular health. Acknowledgements None.

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Compliance with ethical standards Conflict of interest The authors declare that they have no conflicts of interest.

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