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Objective: This study aimed to compare cardiac morphological and functional changes in fetuses of patients with diet-regulated gestational diabetes mellitus (GDM-A1), insulin-regulated GDM (GDM-A2), and a control group., Method: A prospective cohort study included pregnant women aged 18-40 years with singleton pregnancies. Fetal biometric, cardiac morphological, and functional measurements were recorded using Z-scores at 34-37 weeks of gestation., Results: The study included 87 patients. Both right and left ventricular wall thicknesses were significantly different between the three groups (p < 0.001 and p < 0.001, respectively). Z-scores of the mitral valve, left and right EDD were significantly lower in GDM-A1 and GDM-A2 groups compared to the control group (p < 0.001, p < 0.001, p = 0.002, respectively). Right and left ventricular areas were decreased only in GDM-A2 group compared to the control group (p = 0.003 and p = 0.001, respectively). MPI and IVRT values were also significantly higher in the same groups (p = 0.016, p < 0.001, respectively)., Conclusion: Gestational diabetes increased IVS and ventricular wall thicknesses in both right and left ventricles, irrespective of whether it was controlled by diet or insulin. Cardiac functional changes were observed in the GDM-A2 group., (© 2024 Wiley Periodicals LLC.)

Background Fetal diagnosis of congenitally corrected transposition of the great arteries (ccTGA) has been increasingly reported; however, predictors of clinical outcomes remain underexplored. We undertook a multicenter, retrospective study to investigate natural history, associated anomalies, and outcomes of fetal ccTGA. Methods and Results Fetuses with ccTGA diagnosed from January 2004 to July 2020 within 20 North American programs were included. Fetuses with severe ventricular hypoplasia thought to definitively preclude biventricular repair were excluded. We included 205 fetuses diagnosed with ccTGA at a median gestational age of 23 (interquartile range, 21-27) weeks. Genetic abnormalities were found in 5.9% tested, with extracardiac anomalies in 6.3%. Associated cardiac defects were diagnosed in 161 (78.5%), with atrioventricular block in 23 (11.3%). On serial fetal echocardiogram, 39% demonstrated a functional or anatomic change, most commonly increased tricuspid regurgitation (6.7%) or pulmonary outflow obstruction (11.1%). Of 194 fetuses with follow-up, 26 were terminated, 3 experienced fetal death (2 with atrioventricular block), and 165 were live-born. Of 158 with postnatal data (median follow-up 3.7 years), 10 (6.6%) had death/transplant before 1 year. On univariable analysis, fetal factors associated with fetal death or death/transplant by 1 year included ≥ mild tricuspid regurgitation, pulmonary atresia, aortic obstruction, fetal arrhythmia, and worsening hemodynamics on serial fetal echocardiogram (defined as worse right ventricular function, tricuspid regurgitation, or effusion). Conclusions Associated cardiac lesions and arrhythmias are common in fetal ccTGA, and functional changes commonly occur through gestation. Worse outcomes are associated with fetal tricuspid regurgitation (≥mild), any arrhythmia, pulmonary atresia, aortic obstruction, and worsening hemodynamics on serial echocardiograms. These findings can inform prenatal counseling and perinatal management planning.

Background: Fetal dedicated echocardiography is the standard to measure the fetal cardiac axis. However, fetal screening ultrasound (US) or fetal dedicated echocardiography may be technically limited., Objective: The purpose of this study was to explore the accuracy of fetal cardiac magnetic resonance imaging (MRI) to measure the cardiac axis in fetuses with congenital heart disease as an adjunct to fetal dedicated echocardiography and to assess the predictive value of fetal cardiac MRI measurements in distinguishing healthy fetuses from fetuses with congenital heart disease., Materials and Methods: This is a retrospective study of fetuses referred to our hospital for a fetal cardiac MRI from November 2019 to December 2021. Cardiac axes were measured in the 4-chamber view of the fetal heart using fetal cardiac MRI and dedicated echocardiography, or only using fetal cardiac MRI when screening US was technically limited. The fetuses were divided into a congenital heart disease group and a healthy control group. We used Bland-Altman analysis and the intraclass correlation coefficient (ICC) to assess the agreement of cardiac axis measurements in fetuses with congenital heart disease obtained by cardiac MRI and by fetal dedicated echocardiography. Receiver operating characteristic (ROC) curve analysis of the fetal cardiac axes in the congenital heart disease and healthy fetus groups assessed the predictive value of the cardiac axis measurements., Results: This retrospective study included 431 women (162 carrying fetuses with congenital heart disease, 269 carrying healthy fetuses). Cardiac axes were measured in the 162 fetuses with congenital heart disease using fetal cardiac MRI and dedicated echocardiography. Cardiac axes were measured in the 269 healthy control fetuses using fetal cardiac MRI when fetal screening US was technically limited. The interobserver analysis and intraobserver analysis showed that the cardiac axis measured by fetal cardiac MRI and fetal dedicated echocardiography was repeatable (ICC>0.90). In 162 fetuses with congenital heart disease, Bland-Altman analysis showed a strong agreement between cardiac MRI and fetal dedicated echocardiography measurements for the cardiac axis. The ICC for the cardiac axis values between cardiac MRI and fetal dedicated echocardiography measurements was 0.99. In fetuses with congenital heart disease, 64.2% (104/162) had an abnormal cardiac axis. For the fetal cardiac axis in both the 162 fetuses with congenital heart disease and the 269 healthy fetuses, the area under the ROC curve reached 0.85 (95% confidence interval: 0.80-0.89; P<0.0001)., Conclusion: The cardiac axis can be accurately measured using fetal cardiac MRI when fetal dedicated echocardiography/fetal screening US is technically limited. The cardiac axis measurements by fetal cardiac MRI are consistent with known cardiac axis measurements by fetal dedicated echocardiography. The frequency of abnormal cardiac axis depends on the type of congenital heart disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Fetal cardiac magnetic resonance imaging (MRI) requires high spatial and temporal resolution and robustness to random fetal motion to capture the dynamics of the beating fetal heart. Slice-to-volume reconstruction techniques can produce high-resolution isotropic images while compensating for random fetal motion., Objective: The objective of this study was to evaluate image quality for slice-to-volume reconstruction of four-dimensional balanced steady-state free precession (bSSFP) imaging of the fetal heart., Materials and Methods: A cohort of 13 women carrying fetuses with congenital heart disease were imaged with real-time bSSFP sequences. Real-time bSSFP sequences were post-processed using a slice-to-volume reconstruction algorithm to produce retrospectively gated 4-D sequences with isotropic spatial resolution. Two radiologists evaluated slice-to-volume reconstruction image quality on a scale from 0 to 4 using 11 categories based on a segmental approach to defining cardiac anatomy and pathology. A score of 0 corresponded to cardiac structures not visualized at all and four corresponded to high quality and distinct appearance of structures., Results: In 11 out of 13 cases, the average radiologist score of image quality across all categories was 3.0 or greater. In the remaining two cases, slice-to-volume reconstruction was not possible due to insufficient image quality in the acquisition., Conclusion: Slice-to-volume reconstruction has the potential to produce isotropic images with high spatial and temporal resolution that can display the anatomy of the fetal heart in arbitrary imaging planes retrospectively. More rapid, motion-robust acquisitions may be necessary to successfully reconstruct the fetal heart in all patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myocardial ischemia can cause insufficient oxygen and functional damage to myocardial cells. Carbonic anhydrase III (CAIII) has been found to be closely related to the abnormality of cardiomyocytes. To investigate the role of CAIII in the apoptosis of myocytes under hypoxic conditions and facilitate the strategy for treating hypoxia-induced damage, in vitro experiments in H9c2 were employed. The protein expression of CAIII in H9c2 cells after hypoxia or normoxia treatment was determined by western blotting and immunohistochemistry. MTT assay was employed for cells viability measurement and LDH release was monitored. The apoptotic cells were observed using immunofluorescence assay, flow cytometric analysis, and TUNEL assay. CAIII-overexpression or -knockdown cells were constructed to determine the role of CAIII in regulating apoptosis-related proteins caspase-3, Bax, Bcl-2, and anti-apoptosis pathway PI3K/Akt/mTOR. The mRNA levels of CAIII and genes related to CAIII synthesis including REN, IGHM, APOBEC 3F, and SKOR2 were significantly upregulated in hypoxia fetal sheep. The expression of CAIII protein and content of apoptotic H9c2 cells were increased at 1, 3, 6, and 12 h after hypoxia treatment. Overexpression of CAIII significantly upregulated Bcl2 level and downregulated Bax and caspase-3 cleavage levels, while its knockdown led to the contrary results. Overexpressed CAIII promoted the HIF-1α level and activated the PI3K/Akt/mTOR pathway, thereby exerting an inhibitory effect on hypoxia-induced apoptosis. In conclusion, our findings revealed that CAIII could protect cell from hypoxia-apoptosis of H9c2 cells, in which, activated PI3K/Akt/mTOR signaling pathway may be involved., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life., Objective: This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR., Methods: Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes., Results: IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced adenosine 5'-triphosphate production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified the accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids (LCFAs) in IUGR fetal hearts, which leads to nuclear receptor peroxisome proliferator-activated receptor α (PPARα) transcriptional activation in cardiomyocytes. Also, the enrichment of H3K27ac chromatin marks to PPARα-responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch., Conclusion: This study describes a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific LCFAs that may serve as predictive effectors leading to IUGR., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Is the presence of cytoplasmic strings (CS) in human blastocysts associated with the probability of clinical pregnancy with fetal heart (CPFH) after transfer., Methods: This case-control study involved 300 single blastocyst transfers. 150 of these resulted in a CPFH (cases) while 150 did not (controls). All embryos were cultured in Embryoscope+ and AI software (IVY) was used to select the blastocyst with the highest score from the cohort for transfer. An embryologist, blind to the transfer outcome, recorded the CS number, location, and duration of their activity., Results: There was a significant difference in the number of blastocysts that contained CS, with 97.3% of women's blastocysts resulting in +CPFH containing the CS compared to 88.7% of blastocysts in women who did not have a pregnancy (p = 0.007, OR; 4.67, CI 95% 1.5-14.2). CS appeared 2.4 h earlier in embryo development in the +CPFH group compared to their negative counterparts (p = 0.007). There was a significant difference in the average number of CS/blastocyst with a higher number being present in those that achieved a clinical pregnancy (mean: 6.2, SD 2.9) compared to those that did not (mean: 4.6, SD 3.0) (p ≤ 0.0001). There was a significant increase in the number of vesicles seen traveling along the CS with more seen in the blastocysts resulting in a +CPFH (mean: 4.3 SD 2.1) compared to those in the -CPFH group (mean: 3.1, SD 2.1)., Conclusion: This study has shown that the presence of cytoplasmic strings in human blastocysts is associated with the probability of clinical pregnancy with fetal heart., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Right atrial isomerism (RAI) is one of the most severe forms of congenital heart disease. This case of RAI was so complex that it incorporated 7 heart defects. It can be challenging to display the spatial relationship between different anatomical structures using conventional two-dimensional and color ultrasound (2D-Doppler imaging); therefore, we used spatio-temporal image correlation (STIC) and high definition live flow imaging technology to vividly display this case of RAI in a stereoscopic mode., Patient Concerns: A 24-year-old woman was referred to our tertiary center at 24 weeks of gestation. The woman had difficult conceiving. Once pregnant, she was opposed to abortion, even if there was a possibility of deformity., Diagnosis: The fetus presented with an atrioventricular septal defect, persistent left superior vena cava, supra-cardiac total anomalous pulmonary venous connection (TAPVC), double outlet right ventricle, right ductus arteriosus, right aortic arch (RAA) with mirror image branching, and aortic arch dysplasia., Interventions: After consulting a pediatric cardiologist, the woman requested an abortion and consented to an autopsy., Outcomes: Autopsy supported the echocardiographic findings., Lessons: Accurate diagnosis of RAI is essential for clinical and parent decision making. 2D-Doppler imaging combined with STIC-HD live flow can be used to visualize the spatial morphology of blood vessels, including the cardiac chambers and great vessels of the fetal heart, and smaller peripheral vessels., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-β1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.

Background: Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known., Objective: The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses., Materials and Methods: A cross-sectional study was conducted in Fetuses affected by Hb Bart's disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis., Results: Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart's and non-anemic groups. In Bart's group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart's group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart's group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart's group. However, there was no difference in cardiac iron accumulation levels between these two groups., Conclusion: Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart's and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart's., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The developmental exposure to a single chemical may elicit apoptosis in the different fetal organs, while the combined effects are restricted. We have examined the protective role of flaxseed (FS) against diesel exhaust particles (DEPs)- and/or fenitrothion (FNT)-induced fetal cardiac oxidative stress and apoptosis. A total of 48 timed pregnant rats were divided into eight groups (n = 6). The first group was saved as the control and the second fed on 20% FS diet. Animals in the third, fourth, and fifth groups were administered with DEPs (2.0 mg/kg), FNT (3.76 mg/kg), and their combination, respectively, while the sixth, seventh, and eighth groups were supplemented with 20% FS through intoxication with DEPs, FNT, and their combination, respectively. Our results revealed that DEPs and/or FNT significantly elevated the level of protein carbonyl and superoxide dismutase activity in the fetal cardiac tissues. However, the catalase activity and total thiol level were decreased; besides the histopathological alterations were remarked. Moreover, DEPs and/or FNT exhibited significant down-regulation in the anti-apoptotic (Bcl-2) and paraoxonase-1 gene expression, and up-regulation in the apoptotic (Bax and caspase-3) gene expression along with DNA fragmentation. Remarkably, FS supplementation significantly ameliorated the fetal cardiac oxidative injury, down-regulated the expression of the apoptotic genes, up-regulated the anti-apoptotic and paraoxonase-1 gene expression, reduced DNA fragmentation, and alleviated the myocardial cell architectures. These findings revealed that FS attenuates DEPs- and/or FNT-induced apoptotic cell death by repairing the disturbance in the anti-apoptotic/pro-apoptotic gene balance toward cell survival in the fetal myocardial cells.

Aims: Investigating human heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for normal functioning. We investigated foetal human heart single-cell transcriptomes from mid-gestational healthy and anti-SSA/Ro associated congenital heart block (CHB) samples., Methods and Results: Three healthy foetal human hearts (19th to 22nd week of gestation) and one foetal heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single-cell suspensions followed by 10× Genomics- and Illumina-based single-cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse sub-populations of endothelial cells were identified in the human heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types of the CHB heart compared with the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contribute to extracellular matrix deposition and subsequent fibrosis., Conclusion: These data provide an information-rich resource to further our understanding of human heart development, which, as illustrated by comparison to a heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To assess the feasibility of retrieval of intact human fetal hearts after first trimester surgical termination of pregnancy (TOP) and subsequent anatomical assessment by postmortem micro-computed tomography (micro-CT)., Methods: In a cohort of consenting women undergoing surgical TOP between 8 and 13 weeks' gestation, we attempted the retrieval of the fetal heart from the suction material. Specimens were immersion fixed in 10% formaldehyde, scanned by iodine-enhanced micro-CT and cardiac anatomy assessed by a multidisciplinary team using 3D-multiplanar analysis., Results: The median gestational age at TOP was 10.7 weeks (range 8.3-12.9). In 57 (95.0%) out of 60 suction specimens, the heart could be retrieved. The median cardiac length was 5 mm (range 2-8 mm), in three (5.3%), the heart was too damaged to assess cardiac anatomy and in five (8.7%) only the four chambers could be examined. In the remaining 49 (86.0%) cases, a detailed assessment of cardiac anatomy was possible, showing a major defect in two (4.1%) and a minor defect in four (8.2%)., Conclusions: Fetal hearts can be retrieved after first trimester TOP being intact in the vast majority of cases. Iodine-enhanced, postmortem micro-CT can be used to assess cardiac anatomy from as early as 8 weeks and to describe heart abnormalities., (© 2020 John Wiley & Sons, Ltd.)

Studies on the occurrence of segmental aneuploidoidy in fetuses with isolated echogenic intracardiac focus (EIF) are scarce. The aim of this study was to analyze whether there is an association between abnormal segmental aneuploidies and isolated EIF. This was a prospective case-control study. The study participants in the case group were fetuses that were diagnosed with isolated EIF. Samples without fetal ultrasound abnormalities but received prenatal diagnosis for other reasons (serological screening high-risk, voluntary request) were set as controls. All pregnant women were younger than 35 years old at the expected date of childbirth. Copy number variation sequencing (CNV-seq) was performed for all samples. The case group and control group successfully underwent CNV-seq analysis and exhibited 1,099 and 5,616 amniotic fluid samples, respectively. The detection rates of abnormal segmental aneuploidies in the case group and control group were 0.6% (7/1,099) and 1.1% (64/5,616), respectively; no statistically significant difference was found between the two groups (x 2  = 2.220, P = 0.136). Isolated EIF did not increase the risk of fetal segmental aneuploidies.

Objectives: Establish a fetal heart anatomical cross-sectional database that correlates with screening transverse ultrasound images suggested by international professional organizations to detect congenital heart defects., Methods: Fetuses with suspected congenital heart defects identified using the following cardiac image sequences obtained from transverse slices beginning from the upper abdomen and ending in the upper thorax were the subjects of this study: (1) four-chamber view, (2) left ventricular outflow tract view, (3) three-vessel right ventricular outflow tract view, and (4) the three-vessel tracheal view. A database of digital two-dimensional images of the transverse sweep was created for fetuses with confirmed congenital heart defects. In addition, using four-dimensional ultrasound spatial-temporal image correlation, selected transverse ultrasound images were acquired as part of the database. Ultrasound-detected congenital heart defects were confirmed postnatally from pathological specimens of the heart and lungs using a cross-sectional technique that mirrored the ultrasound images described above. When anatomical specimens were not available, prenatal ultrasound-detected congenital heart defects were confirmed using postnatal echocardiography and/or following surgery., Results: The four screening views described in the Methods section identified 160 fetuses that comprised the database. Forty-five datasets consisted of both ultrasound and anatomical cross-sectional images. Thirteen percent (6/45) only had abnormalities of the four-chamber view (eg, endocardial cushion defects). Twenty-four percent (11/45) had abnormalities of the four-chamber view as well as right and left outflow tracts (eg, complex malformations). Of these, 10 of 11 had an abnormal tracheal view. Sixteen percent (7/45) had an abnormal four-chamber view and abnormal right outflow tract (eg, pulmonary stenosis). Thirty-three percent (15/45) had a normal four-chamber view but had abnormal right and left outflow tracts as well as an abnormal tracheal view (eg, tetralogy of Fallot, D-transposition of the great arteries)., Conclusions: Combining both ultrasound and anatomical imaging may be of assistance in training imagers to recognize cardiovascular pathology when performing the screening examination of the fetal heart., (© 2020 John Wiley & Sons, Ltd.)

Persistent left superior vena cava (PLSVC) is one of the cardiac system abnormalities with a 0.3-0.5% incidence and caused by inadequate obliteration of the left anterior cardinal vein during embryonic development. Prognosis of PLSVC is generally assumed to be good if it is not accompanied by other cardiac system abnormalities. During the routine ultrasound control of a patient at 25th week of pregnancy at the Obstetrics and Gynecology Department of Mersin University, PLSVC anomaly was detected in an intrauterine fetus. Then, intrauterine death occurred and after removal of the deceased fetus, PLSVC diagnosis was confirmed by autopsy. According to the autopsy findings, right superior vena cava (SVC) and azygos vein were found in normal course. PLSVC opened into the right atrium via enlarged coronary sinus. There was no connection between the two SVCs. On the left side of posterior mediastinum, instead of hemiazygos or accessory hemiazygos veins, a vein symmetrical to azygos was opened into PLSVC, similar to the one on the right. No other cardiac anomaly associated with PLSVC or any other pathology in the other parts of body that could be responsible for death was discovered during autopsy. There was no evidence indicating that PLSVC played any role in intrauterine exitus of the present case. However, as mentioned in the literature, the ectopic beats in the atrium wall of patients with isolated PLSVC and enlarged coronary sinus may lead to pathologies in the conduction system of the heart. Considering the intrauterine death of an isolated PLSVC case associated with cardiac conduction pathologies, we recommend that the common assumption of 'isolated PLSVC is not associated with death' should be reviewed by studies on large series and even intrauterine cases should be closely monitored for cardiac arrhythmia.

Coarctation of the aorta (COA) is suspected prenatally when there is ventricular asymmetry, arterial disproportion, and hypoplasia of the aortic arch/isthmus. The presence of fetal shunts creates difficulty in prenatal confirmation of the diagnosis so serial echocardiography after birth is necessary to confirm or refute the diagnosis. The first neonatal echocardiogram in prenatally suspected cases of COA was assessed for prediction of neonatal COA repair (NCOAR). This included morphological assessment, measurement of the aortic arch and calculation of the distal arch index (DAI = distance between left common carotid and left subclavian artery/diameter of the distal arch). NCOAR was undertaken in 23/60 (38%) cases. Transverse arch, aortic isthmus z-score, and DAI had an area under the receiver operator curve of 0.88 (95% CI 0.77-0.98), 0.86 (95% CI 0.75-0.96), and 0.84 (95% CI 0.74-0.95), respectively for the prediction of NCOAR. Using transverse arch z-score threshold < - 3 gave sensitivity 100%, NPV: 100%, specificity 76%; aortic isthmus z-score  < - 3: NPV 92%, specificity 62% and DAI > 1.4: NPV 88%, specificity 78%. The size of the distal aortic arch in infants with a common origin of the innominate artery and left common carotid artery who did not require COA repair was similar to the NCOAR cases (p = 0.22). The early postnatal assessment of the size and morphology of the aortic arch can assist in risk stratification for development of neonatal COA. The branching pattern of the head/neck vessels impacts on the size of the distal aortic arch adding to the complexity of predicting COA based on vessel size.

Introduction: The clinical importance of mass effect from congenital lung masses on the fetal heart is unknown. We aimed to report cardiac measurements in fetuses with congenital lung masses and to correlate lung mass severity/size with cardiac dimensions and clinical outcomes., Methods: Cases were identified from our institutional database between 2009 and 2016. We recorded atrioventricular valve (AVVz) annulus dimensions and ventricular widths (VWz) converted into z scores, ratio of aortic to total cardiac output (AoCO), lesion side, and congenital pulmonary airway malformation volume ratio (CVR). Respiratory intervention (RI) was defined as intubation, extracorporeal membrane oxygenation (ECMO), or use of surgical intervention prior to discharge., Results: Fifty-two fetuses comprised the study cohort. Mean AVVz and VWz were below expected for gestational age. CVR correlated with ipsilateral AVVz (R S = -.59, P < .001) and ipsilateral VWz (-0.59, P < .001). Lower AVVz and AoCO and higher CVR were associated with RI. No patient had significant structural heart disease identified postnatally., Conclusion: In fetuses with left-sided lung masses, ipsilateral cardiac structures tend to be smaller, but in our cohort, there were no patients with structural heart disease. However, smaller left-sided structures may contribute to the need for RI that affects a portion of these fetuses., (© 2019 John Wiley & Sons, Ltd.)

The prevalence of coronary intimal thickening (IT) was assessed in fetuses and pediatric population. We studied the coronary arteries of 63 hearts obtained from fetuses, infants, children, and adolescents, deceased from noncardiac disease or trauma. Histomorphometric analysis, planimetry, and immunohistochemical studies were conducted. Intimal thickening consisted of proliferation of smooth muscle cells and scarce monocytes embedded in amorphous deposits within the internal elastic membrane (IEM). Intermingled lesions of intimal hyperplasia and parietal nonstenotic plaques were also observed. Intimal thickening was found in 10% of 20 fetuses, in 33.3% of 18 infants, 73.3% of 15 children, and 100% of 10 adolescents. A significant correlation ( r = 0.671, P < 0.001) was found between the extent of IT and age. The IEM was duplicated or interrupted in 43% of patients, showing a positive correlation with the degree of IT ( P = 0.01). Intimal thickening was predominantly found near bifurcation sites in the left anterior descending coronary artery (55.6%) and in zones free of bifurcation in the right coronary artery (75%). In conclusion, the prevalence and extension of IT lesions are higher at older ages within a young population. Intimal thickening may be regarded as the first event occurring in coronary preatherosclerosis, preceding lipid deposition.

Myoarchitectural disarray - the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild-type, heterozygous and homozygous hearts (n = 56) from a Mybpc3-targeted knock-out HCM mouse model and imaged the 3D micro-structure by high-resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild-type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild-type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild-type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH., (© 2019 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Objective: Evaluate fetal echocardiography's ability to detect critical (lesions requiring immediate neonatal intensive care) congenital heart disease (CHD) after normal anatomic cardiac views on detailed ultrasound., Methods: Singletons with both a detailed ultrasound at 18 + 0 to 22 + 6 weeks and echocardiogram performed at least 14 days later and at 20 + 0 to 24 + 6 weeks. Cases with cardiac pathology on detailed ultrasound were excluded. Different combinations of cardiac views were described: Basic (four-chamber, outflow tracts), Expanded (plus three-vessel view), and Complete (plus ductal/aortic arches). "Normal" was defined on either 2D gray scale or color Doppler. Primary outcome was rates of critical CHD missed on ultrasound but seen on fetal echocardiogram., Results: One thousand two hundred twenty-three women had normal Basic cardiac views. One thousand one hundred ninety (97.3%) were confirmed normal on echocardiogram. Twenty-one (1.71%) total CHDs were missed, and three were critical (0.25%; 95% CI, 0.03%-0.53%). Of the 1,223 women, 763 had Complete views. Ten (1.31%) total CHDs were missed and one (0.13%; 95% CI, 0.13%-0.36%) was confirmed critical., Conclusion: Fetal echocardiography can increase CHD detection despite normal cardiac anatomy on detailed ultrasound; however, CHDs missed are rarely critical. Approximately 750 fetal echocardiograms need to be performed to detect one critical CHD with Complete normal cardiac views on detailed ultrasound., (© 2019 John Wiley & Sons, Ltd.)

Objective: Redistribution of cardiac output is responsible for the "brain sparing" effect seen during periods of acute or chronic fetal stress. We investigated the relationship between prelabour cardiac function in fetuses that subsequently developed intrapartum fetal compromise (IFC). Methods: A blinded, prospective, observational, cohort study, at Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent ultrasound every 2 weeks from 36 weeks until delivery. Fetal cardiac output was assessed by conventional Doppler ultrasound and myocardial deformation was measured using velocity vector imaging. Results: Two hundred and seventy three women were included in the final analysis, of which 19% had an emergency operative delivery for intrapartum fetal compromise (IFC). Global left ventricular strain (-12.1%, interquartile ranges (IQR) - 10.3 to -14% versus 13%, IQR -11.3 to -14.2%, p  = .01) and strain rate (-1.00, IQR 0.85-1.16 s -1 versus -1.11, IQR -1.00 to -1.21 s -1 , p  < .001) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not. Global longitudinal right ventricular strain rate was lower in fetuses that developed IFC (-1.04 ± 0.22 s -1 versus 1.13 ± 0.22 s -1 , p  < .001), whereas global right ventricular strain did not show any significance differences between the two groups. Additionally, left ventricular cardiac output was lower in fetuses that developed IFC or had a composite neonatal morbidity (560 ± 44 mL/min versus 617 ± 72 mL/min, p  < .001) or (581 ± 44 mL/min versus 612 ± 72 mL/min, p  < .01), respectively. Conclusion: Lower global left ventricular strain and strain rate and cardiac output are associated with IFC and poorer condition of the newborn. Assessment of fetal cardiac function may be useful for risk stratification for intrapartum fetal compromise in apparently "low risk" term pregnancies.

Objective: To analyze the imaging and clinical features of fetal cardiac tumors, and to explore the relationship between tuberous sclerosis complex (TSC) and cardiac rhabdomyoma in the fetus., Methods: Fifty-three women pregnant with a fetus affected by cardiac tumor(s) were examined by standardized fetal echocardiography (FE), and fetuses, mothers and fathers, including other relevant family members if necessary, underwent familial TSC genetic testing. Relevant pathological features, including pathological findings at clinical examination of liveborn infants and autopsy findings in terminated cases, were noted., Results: Of the 53 fetuses, 37 had multiple cardiac tumors and 16 had a single cardiac tumor detected by FE. In all 53 fetuses and their families, TSC genetic testing was successful, showing that 37 of the fetuses had a TSC1 (n = 6) or TSC2 (n = 31) pathogenic or suspected pathogenic mutation, of which 25 were spontaneous and 12 were familial mutations. The proportion of single and multiple cardiac tumors at FE was significantly different between the group of fetuses with positive genetic test results and that with negative results for TSC (31% and 86%, respectively), although the presence of multiple or single tumors was not associated with the type of TSC mutation. The decision to terminate the pregnancy was made by 45 women and their families, and eight fetuses were liveborn. Autopsy was performed in 38 fetuses, which revealed 36 cases with pathologically confirmed cardiac rhabdomyoma, one case of hemangioma and one case of fibroma. 93% of fetuses with multiple rhabdomyomas at autopsy and 71% of those with a single cardiac rhabdomyoma harbored a TSC1 or TSC2 mutation., Conclusion: Cardiac rhabdomyoma is the most common cardiac tumor in the fetus. The correlation between cardiac rhabdomyoma and TSC is strong regardless of the presence of single or multiple tumors. For fetuses with suspected cardiac rhabdomyoma identified by FE, prenatal genetic testing for TSC of both fetus and family members is recommended. A positive genetic diagnosis can help in counseling and planning for neonatal treatment. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Chronic intrauterine hypoxia is a programming stimulus of cardiovascular dysfunction. While the fetal heart adapts to the reduced oxygenation, the offspring heart becomes vulnerable to subsequent metabolic challenges as an adult. Cardiac mitochondria are key organelles responsible for an efficient energy supply but are subject to damage under hypoxic conditions. We propose that intrauterine hypoxia alters mitochondrial function as an underlying programming mechanism of contractile dysfunction in the offspring. Indices of mitochondrial function such as mitochondrial DNA content, Complex (C) I-V expression, and CI/CIV enzyme activity were measured in hearts of male and female offspring at 90 days old exposed to prenatal hypoxia (10.5% O 2 ) for 14 d prior to term (65 d). Both left ventricular tissue and cardiomyocytes exhibited decreased mitochondrial DNA content, expression of CIV, and CI/CIV activity in male hearts. In female cardiomyocytes, hypoxia had no effect on protein expression of CI-CV nor on CI/CIV activity. This study suggests that chronic intrauterine hypoxia alters the intrinsic properties of select respiratory complexes as a programming mechanism of cardiac dysfunction in the offspring. Sex differences in mitochondrial function may underlie the increased vulnerability of age-matched males compared to females in cardiovascular disease and heart failure.

Background: Fetal aortic stenosis (AoS) may progress to hypoplastic left heart syndrome (HLHS) in utero. There are currently no data, prenatal or postnatal, describing survival of fetuses or neonates with AoS or HLHS in a country with suboptimal postnatal management., Study Design: Prospective cohort study performed in Mexico, including cases diagnosed with AoS and HLHS within a 6-year period. AoS patients fulfilling previously published criteria for evolving HLHS (eHLHS) were offered fetal aortic valvuloplasty. Outcome variables were perinatal mortality, postnatal management, type of postnatal circulation, and overall survival., Results: Fifty-four patients were included: 16 AoS and 38 HLHS. Eighteen patients had associated anomalies and/or an abnormal karyotype. Seventy-four percent of HLHS received comfort measures, with only three cases reporting an attempt at surgical palliation, and one survivor of the first stage. Fetal aortic valvuloplasty was performed successfully in nine cases of eHLHS. Overall postnatal survival was 44% in AoS with fetal aortic valvuloplasty, and one case (ongoing) in the HLHS group., Conclusions: HLHS in Mexico carries more than a 95% risk of postnatal death, with little or no experience at surgical palliation in most centers. Fetal aortic valvuloplasty in AoS may prevent progression to HLHS and in this small cohort was associated with ≈50% survival., (© 2019 John Wiley & Sons, Ltd.)

Backgrounds: Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice., Methods: The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR., Results: Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group., Conclusion: Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice., Competing Interests: The authors have declared that no competing interests exist.

Objectives: This study was conducted to evaluate left ventricular (LV) size and function in healthy fetuses and to test a cohort of fetuses at risk for abnormal function using speckle-tracking software., Methods: Two hundred control fetuses were examined between 20 and 40 weeks' gestation. With the use of offline speckle-tracking software, the end-diastolic and end-systolic volumes were measured and the following computed: stroke volume (SV), SV per kilogram, cardiac output (CO), CO per kilogram, and ejection fraction. These were regressed against 7 independent variables related to the size, weight, and age of the fetuses. Five fetuses with risk factors for LV dysfunction were examined to sample the validity of the data from the control group., Results: The R 2 values for measurements of the end-diastolic volume, SV, and CO correlated with the 7 independent variables of fetal size and age (0.7-0.78), whereas the SV/kg, CO/kg, and ejection fraction had lower R 2 values (0.02-0.1). The measurements were normally distributed (Shapiro-Wilke > 0.5). The 5 fetuses at risk for abnormal LV function had measurements of LV size and function that were consistent with the expected pathologic condition., Conclusions: Speckle tracking can provide a comprehensive evaluation of the size and function of the fetal LV., (© 2018 by the American Institute of Ultrasound in Medicine.)

The fetal myocardium is known to be sensitive to hemodynamic load, responding to systolic overload with cellular hypertrophy, proliferation, and accelerated maturation. However, the fetal cardiac growth response to primary volume overload is unknown. We hypothesized that increased venous return would stimulate fetal cardiomyocyte proliferation and terminal differentiation, particularly in the right ventricle (RV). Vascular catheters and pulmonary artery flow probes were implanted in 16 late-gestation fetal sheep: a right carotid artery-jugular vein (AV) fistula was surgically created in nine fetuses, and sham operations were performed on seven fetuses. Instrumented fetuses were studied for 1 wk before hearts were dissected for component analysis or cardiomyocyte dispersion for cellular measurements. Within 1 day of AV fistula creation, RV output was 20% higher in experimental than sham fetuses ( P < 0.0001). Circulating atrial natriuretic peptide levels were elevated fivefold in fetuses with an AV fistula ( P < 0.002). On the terminal day, RV-to-body weight ratios were 35% higher in the AV fistula group ( P < 0.05). Both left ventricular and RV cardiomyocytes grew longer in fetuses with an AV fistula ( P < 0.02). Cell cycle activity was depressed by >50% [significant in left ventricle ( P < 0.02), but not RV ( P < 0.054)]. Rates of terminal differentiation were unchanged. Based on these studies, we speculate that atrial natriuretic peptide suppressed fetal cardiomyocyte cell cycle activity. Unlike systolic overload, fetal diastolic load appears to drive myocyte enlargement, but not cardiomyocyte proliferation or maturation. These changes could predispose to RV dysfunction later in life. NEW & NOTEWORTHY Adaptation of the fetal heart to changes in cardiac load allows the fetus to maintain adequate blood flow to its systemic and placental circulations, which is necessary for the well-being of the fetus. Addition of arterial-venous fistula flow to existing venous return increased right ventricular stroke volume and output. The fetal heart compensated by cardiomyocyte elongation without accelerated cellular maturation, while cardiomyocyte proliferation decreased. Even transient volume overload in utero alters myocardial structure and cardiomyocyte endowment.

Objective: To evaluate the effect of fetal growth restriction (FGR) at term on fetal and neonatal cardiac geometry and function., Methods: This was a prospective study of 87 pregnant women delivering at term, comprising 54 normally grown and 33 FGR pregnancies. Fetal and neonatal conventional and spectral tissue Doppler and two-dimensional speckle tracking echocardiography were performed a few days before and within hours after birth. Fetal cardiac geometry, global myocardial deformation and performance and systolic and diastolic function were compared between normal and FGR pregnancies before and after birth., Results: Compared with normally grown fetuses, FGR fetuses exhibited more globular ventricular geometry and poorer myocardial deformation and cardiac function (left ventricular (LV) sphericity index (SI), 0.54 vs 0.49; right ventricular (RV) SI, 0.60 vs 0.54; LV torsion, 1.2 °/cm vs 3.0 °/cm; LV isovolumetric contraction time normalized by cardiac cycle length, 121 ms vs 104 ms; interventricular septum early diastolic myocardial peak velocity/atrial contraction myocardial diastolic peak velocity ratio, 0.60 vs 0.71; P < 0.01 for all). The poorest perinatal outcomes occurred in FGR fetuses with the most impaired cardiac functional indices. When compared with normally grown neonates, FGR neonates showed persistent alteration in cardiac parameters (LV-SI, 0.53 vs 0.50; RV-SI, 0.54 vs 0.44; LV torsion, 1.1 °/cm vs 1.4 °/cm; LV myocardial performance index (MPI'), 0.52 vs 0.42; P < 0.01 for all). Paired comparison of fetal vs neonatal cardiac indices in FGR demonstrated that birth was associated with a significant improvement in some, but not all, cardiac indices (RV-SI, 0.60 vs 0.54; RV-MPI', 0.49 vs 0.39; P < 0.001 for all)., Conclusions: Compared with normal pregnancies, FGR fetuses and neonates at term exhibit altered cardiac indices indicative of myocardial impairment that reflect adaptation to placental hypoxemia and alterations in hemodynamic load around the time of birth. Elucidating potential mechanisms that contribute to the alterations in perinatal cardiac adaptation in FGR could improve management and aid the development of better therapeutic strategies to reduce the risk of adverse pregnancy outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

Congenital heart disease is the most common birth defect, affecting 1.35 million newborns every year. Heart failure is a primary cause of late morbidity and mortality after myocardial infarction. Heart development is involved in several rounds of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET). Errors in these processes contribute to congenital heart disease, and exert deleterious effects on the heart and circulation after myocardial infarction. The identification of factors that are involved in heart development and disease, and the development of new approaches for the treatment of these disorders are of great interest. G protein coupled receptors (GPCRs) comprise 40% of clinically used drug targets, and their signaling are vital components of the heart during development, cardiac repair and in cardiac disease pathogenesis. This review focuses on the importance of EMT program in the heart, and outlines the newly identified GPCRs as potential therapeutic targets of reprogramming EMT to support cardiac cell fate during heart development and after myocardial infarction. More specifically we discuss prokineticin, serotonin, sphingosine-1-phosphate and apelin receptors in heart development and diseases. Further understanding of the regulation of EMT/MET by GPCRs during development and in the adult hearts can provide the following clinical exploitation of these pathways., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Two-dimensional (2D) ultrasound echocardiography is the primary technique used to diagnose congenital heart disease before birth. There is, however, a longstanding need for a reliable form of secondary imaging, particularly in cases when more detailed three-dimensional (3D) vascular imaging is required, or when ultrasound windows are of poor diagnostic quality. Fetal MRI, which is well established for other organ systems, is highly susceptible to fetal movement, particularly for 3D imaging. The objective of this study was to investigate the combination of prenatal MRI with novel, motion-corrected 3D image registration software, as an adjunct to fetal echocardiography in the diagnosis of congenital heart disease., Methods: Pregnant women carrying a fetus with known or suspected congenital heart disease were recruited via a tertiary fetal cardiology unit. After initial validation experiments to assess the general reliability of the approach, MRI data were acquired in 85 consecutive fetuses, as overlapping stacks of 2D images. These images were then processed with a bespoke open-source reconstruction algorithm to produce a super-resolution 3D volume of the fetal thorax. These datasets were assessed with measurement comparison with paired 2D ultrasound, structured anatomical assessment of the 2D and 3D data, and contemporaneous, archived clinical fetal MRI reports, which were compared with postnatal findings after delivery., Findings: Between Oct 8, 2015, and June 30, 2017, 101 patients were referred for MRI, of whom 85 were eligible and had fetal MRI. The mean gestational age at the time of MRI was 32 weeks (range 24-36). High-resolution (0·50-0·75 mm isotropic) 3D datasets of the fetal thorax were generated in all 85 cases. Vascular measurements showed good overall agreement with 2D echocardiography in 51 cases with paired data (intra-class correlation coefficient 0·78, 95% CI 0·68-0·84), with fetal vascular structures more effectively visualised with 3D MRI than with uncorrected 2D MRI (657 [97%] of 680 anatomical areas identified vs 358 [53%] of 680 areas; p<0·0001). When a structure of interest was visualised in both 2D and 3D data (n=358), observers gave a higher diagnostic quality score for 3D data in 321 (90%) of cases, with 37 (10%) scores tied with 2D data, and no lower scores than for 2D data (Wilcoxon signed rank test p<0·0001). Additional anatomical features were described in ten cases, of which all were confirmed postnatally., Interpretation: Standard fetal MRI with open-source image processing software is a reliable method of generating high-resolution 3D imaging of the fetal vasculature. The 3D volumes produced show good spatial agreement with ultrasound, and significantly improved visualisation and diagnostic quality compared with source 2D MRI data. This freely available combination requires minimal infrastructure, and provides safe, powerful, and highly complementary imaging of the fetal cardiovascular system., Funding: Wellcome Trust/EPSRC Centre for Medical Engineering, National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Polycystic ovary syndrome is a complex and common disorder in women, and those affected experience an increased burden of cardiovascular disease. It is an intergenerational syndrome, as affected women with high androgen levels during pregnancy "program" fetal development, leading to a similar phenotype in their female offspring. The effect of excess maternal testosterone exposure on fetal cardiomyocyte growth and maturation is unknown. Pregnant ewes received biweekly injections of vehicle (control) or 100 mg testosterone propionate between 30 and 59 days of gestation (early T) or between 60 and 90 days of gestation (late T). Fetuses were delivered at ~135 days of gestation, and their hearts were enzymatically dissociated to measure cardiomyocyte growth (dimensional measurements), maturation (proportion binucleate), and proliferation (nuclear Ki-67 protein). Early T depressed serum insulin-like growth factor 1 and caused intrauterine growth restriction (IUGR; P < 0.0005). Hearts were smaller with early T ( P < 0.001) due to reduced cardiac myocyte maturation ( P < 0.0005) and proliferation ( P = 0.017). Maturation was also lower in male than female fetuses ( P = 0.004) independent of treatment. Late T did not affect cardiac growth. Early excess maternal testosterone exposure depresses circulating insulin-like growth factor 1 near term and causes IUGR in both female and male offspring. These fetuses have small, immature hearts with reduced proliferation, which may reduce cardiac myocyte endowment and predispose to adverse cardiac growth in postnatal life. While excess maternal testosterone exposure leads to polycystic ovary syndrome and cardiovascular disease in female offspring, it may also predispose to complications of IUGR and cardiovascular disease in male offspring. NEW & NOTEWORTHY Using measurements of cardiac myocyte growth and maturation in an ovine model of polycystic ovary syndrome, this study demonstrates that early gestation excess maternal testosterone exposure reduces near-term cardiomyocyte proliferation and maturation in intrauterine growth-restricted female and male fetuses. The effect of testosterone is restricted to exposure during a specific period early in pregnancy, and the effects appear mediated through reduced insulin-like growth factor 1 signaling. Furthermore, male fetuses, regardless of treatment, had fewer mature cardiomyocytes than female fetuses.

Placental insufficiency causes intrauterine growth restriction (IUGR), a common complication of pregnancy. In skeletal muscle, IUGR reduces fetal myofibril size, reduces myoblast proliferation and reduces expression of genes in cell cycle regulation clusters. The myocardium is striated like skeletal muscle, and IUGR also reduces cell cycle activity and maturation in cardiomyocytes, despite cardiac output preferentially directed to the coronary circulation. We hypothesized that cardiomyocyte growth restriction would be accompanied by similar changes in cell cycle regulation genes and would reduce cardiomyocyte cell cycle activity, number, maturity and size. Pregnant ewes were housed in elevated ambient temperatures from ~40 to ~115 days of gestation (dGA) to produce placental insufficiency and IUGR; fetal hearts were studied at ~134 dGA. Hearts were biopsied for mRNA analysis and then dissociated into individual myocytes (Control n = 8; IUGR n = 15) or dissected (Control n = 9; IUGR n = 13). IUGR fetuses had low circulating insulin and insulin-like growth factor 1 (IGF1) and high circulating cortisol. Bodies and hearts of IUGR fetuses were lighter than those of Controls. Cardiomyocytes of IUGR fetuses were smaller, less mature, less active in the cell cycle and less numerous than in Controls. Further, there was a pattern of downregulation of cell cycle genes in IUGR ventricles. IUGR growth profiles in heart and skeletal muscle suggest similar regulation despite differences in blood and nutrient delivery prioritization. IGF1 signaling is suggested as a mechanism regulating altered growth in IUGR striated muscle and a potential therapeutic candidate.

Aims: To determine if atrial tissue deformation (peak strain, PS) and time to peak strain (TTPS) can be assessed in the fetus, with identification of best echocardiographic plane., Materials and Methods: Pulsed-wave tissue Doppler study of a longitudinal and a transverse four-chamber view (FCV) in each of 20 healthy fetuses. Determination of PS and TTPS in regions of interest (ROI), viz., lateral walls of the right and left atria (RA, LA); comparison of values depending on section plane, with results-based discussion of the physiology of fetal atrial deformation and of possible clinical uses., Results: PS and TTPS could be determined on transverse FCV in 91% of subjects and in 61% on longitudinal FCV. Transverse PS and TTPS were significantly higher than longitudinal (p = 0.0001). Transverse PS was significantly higher in RA than in LA (26.9% vs. 17.3%, p = 0.034), and transverse TTPS was significantly shorter in RA than in LA (p = 0.034)., Conclusion: Atrial radial PS and TTPS determinations are possible in the fetus. The transverse FCV is best suited for these. The highest PS values and shortest TTPS values are found in ROI representing the RA. Our findings may contribute to detailed intrauterine assessment of atrial and ventricular myocardial function., Competing Interests: The authors have declared that no competing interests exist.

Non-compaction cardiomyopathy is a heterogeneous and complex entity concerning which there are still many doubts to be resolved. While the American Heart Association includes it among genetic cardiomyopathies, the European Society of Cardiology treats it as an unclassified cardiomyopathy. It may present in a sporadic or familial form, isolated or associated with other heart diseases, affecting only the left ventricle or both and can sometimes appear as a mixed phenotype in patients with other cardiomyopathies. Different forms of clinical presentation are also associated with its different morphological manifestations, and even non-compaction of the left ventricle may be triggered by other physiological or pathological processes. The purpose of this review is an update of this entity and its controversies., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

The epicardium, an epithelial cell layer covering the myocardium, has an essential role during cardiac development, as well as in the repair response of the heart after ischemic injury. When activated, epicardial cells undergo a process known as epithelial to mesenchymal transition (EMT) to provide cells to the regenerating myocardium. Furthermore, the epicardium contributes via secretion of essential paracrine factors. To fully appreciate the regenerative potential of the epicardium, a human cell model is required. Here we outline a novel cell culture model to derive primary epicardial derived cells (EPDCs) from human adult and fetal cardiac tissue. To isolate EPDCs, the epicardium is dissected from the outside of the heart specimen and processed into a single cell suspension. Next, EPDCs are plated and cultured in EPDC medium containing the ALK 5-kinase inhibitor SB431542 to maintain their epithelial phenotype. EMT is induced by stimulation with TGFβ. This method enables, for the first time, the study of the process of human epicardial EMT in a controlled setting, and facilitates gaining more insight in the secretome of EPDCs that may aid heart regeneration. Furthermore, this uniform approach allows for direct comparison of human adult and fetal epicardial behavior.

We examined the foetal cardiac structural and functional characteristics in diabetic pregnancies versus non-diabetic, healthy pregnancies. Between August 2015 and April 2016, 32 pregnant women with pregestational diabetes, 36 pregnant women with gestational diabetes, and 42 healthy pregnant women were scheduled to have foetal echocardiograms to assess cardiac structure and function. In the diabetic groups, the foetal interventricular septum (IVS) thickness was significantly greater than in non-diabetics (p < .05) but none had an IVS >2 SD from normal. The peak velocity of tricuspid E, and the E/A ratio were significantly lower in the diabetic groups (p < .05). Tricuspid valve E a values and the E a /A a ratio were lower in the diabetic group than in the control group (p < .05) but there was no significant difference between the pre-GDM and GDM groups (p > .05). Interventricular septal hypertrophy is the most common structural abnormality in diabetic pregnancies. These changes do not pose a risk to the foetal unless they cause functional impairment. Thus, we believe that it is important for diabetic pregnant women to be monitored for foetal cardiac diastolic dysfunction. Impact statement What is already known on this subject? Pregestational insulin-dependent diabetes mellitus is a relatively common condition in pregnancy, affecting up to 0.5% of the pregnant population. Foetuses of diabetic mothers are at an increased risk of perinatal morbidity and death. Gestational diabetes mellitus is under-recognised and affects up to 4% of pregnancies. Although diabetes mellitus is known to increase the risk of cardiovascular defects and structural changes (myocardial hypertrophy and diastolic dysfunction) due to foetal hyperglycaemia and hyperinsulinism, similar data in women with gestational diabetes is scarce. Moreover, the effect of maternal hyperglycaemia on foetal cardiac structure and function is unclear because of discordant results from previous studies. What do the results of this study add? In this study, we have used foetal echocardiography, two-dimensional US, pulsed wave Doppler and TDI to characterise the foetal cardiac structure and function in normal pregnancies as well as in the pregnancies complicated by GDM, and pregestational DM. Interventricular septum thickness is increased in women with pregestational diabetes mellitus and impaired diastolic function. The dominant right ventricle of the foetal circulation was affected earlier than the left ventricle. What are the implications of these findings for clinical practice and/or further research? Large population-based studies are required to establish the absolute risk of congenital heart defects in patients with pregestational diabetes and pregestational diabetes in the utility of routine screening.

This review aimed at comprehensively summarizing current available reports regarding the ultrasound markers and biomarkers in predicting fetal Hb Bart's disease and evaluate the potential role of cardiac function assessment in a clinical practice. This review involves various methods in prenatal predicting fetal Hb Bart's disease or alpha-thalassemia major and attempts to provide valuable insights regarding the underlying mechanisms responsible for heart failure in Hb Bart's fetuses. Moreover, this information may be used to predict the cardiac function before the development of hydrops fetalis. Finally, the affected Hb Bart's fetus could be the best model of the study on cardiovascular response to fetal anemia, thus the cardiovascular ultrasound and molecular assessment may be helpful in predicting the prognosis or in making a choice in the management of the fetal anemia condition. In conclusion, ultrasound findings especially cardiomegaly and an increase in peak systolic velocity of the middle cerebral artery (MCA-PSV) are helpful in predicting the future hydrops fetalis and ultrasound assessment of fetal cardiac function is potentially helpful in clinical practice. Finally, this review highlights the pathogenesis of hydropic changes secondary to fetal anemia.

Fetal cardiac tumors are rare and usually benign. While echocardiography is a reliable technique for diagnosing fetal cardiac tumors, their definitive diagnosis relies on pathological examination. The strategies used to manage fetal cardiac tumors are challenging. A good clinical result is their complete regression during pregnancy or shortly after birth, as often occurs with cardiac rhabdomyomas. Moreover, the fetal prognosis depends on the nature of the tumors, namely, their location, size, number and associated complications. The active treatment options for symptomatic fetuses depend on the fetal status and may include fetal open surgery, postnatal tumor resection with or without the bridge of intrauterine pericardiocentesis, and thoracoamniotic shunting. The ex utero intrapartum treatment procedure provides an alternative technique for performing fetal open surgery and has shown promising preliminary results in selected cases, but is invasive for both the mother and fetus.

Purpose: To investigate the relationship between the location of echogenic intracardiac foci (EIFs) and fetal cardiac anomalies in our patient population., Methods: We performed a retrospective study of the clinical files of fetuses who underwent an echocardiographic examination at our fetal cardiac medical center from August 2010 to August 2016. Fetuses were grouped by EIF location (left ventricle [LV], right ventricle [RV], or bilateral ventricles [BVs]). The maternal age, reason for referral, and cardiac anomalies in the three groups were analyzed., Results: We enrolled 2647 fetuses with an EIF. Of these, 2498 (94.4%) were in the LV group, while 45 (1.7%) and 104 (3.9%) were in the RV and BV groups, respectively. Aneuploidy was found in 3 fetuses, and all of these had a left-sided EIF. Cardiac anomalies were found in 93/2498 (3.7%) fetuses with a left-sided EIF, 5/45 (11.1%) of those with a right-sided EIF, and 3/104 (2.9%) of those with bilateral EIFs. The prevalence of congenital heart disease was significantly higher in fetuses with a right-sided EIF than in those with left-sided or bilateral EIFs (P < .05)., Conclusions: Right-sided EIFs were more frequently associated with fetal cardiac anomalies than were left-sided or bilateral EIFs., (© 2017 Wiley Periodicals, Inc.)

Background: In contrast to adults, the fetal response to myocardial infarction (MI) is regenerative, requiring the recruitment of cardiac progenitor cells to replace infarcted myocardium. Macrophage contribution to tissue repair depends on their phenotype: M1 are proinflammatory and initiate angiogenesis; M2a are profibrotic and contribute to blood vessels maturation; and M2c are proremodeling and proangiogenesis. The goal of the present study was to expand on this work by examining cardiac progenitor cells recruitment, and the role of macrophages in promoting angiogenesis and cardiac regeneration in the fetal heart after MI., Methods: Fetal and adult sheep underwent MI and were sacrificed 3 or 30 days after MI. Some fetal hearts received stromal cell-derived factor-1α-inhibitor treatment. The microvasculature was evaluated by micro-computed tomography, gene expression was evaluated by real-time polymerase chain reaction, and vessels counts were evaluated by immunohistochemistry., Results: Micro-computed tomography analysis showed restoration of microvasculature in fetal hearts after MI. Vascular endothelial growth factor-α increased, and the expression of tissue markers associated with the M1, M2a, and M2c macrophage phenotypes were elevated at day 3 after MI, but returned to baseline by 30 days after MI. In contrast, adult hearts after MI exhibited low vascular endothelial growth factor-α and persistent upregulation of all macrophage markers, consistent with prolonged inflammation, fibrosis, and remodeling. Inhibition of stromal cell-derived factor-1α in fetal infarcts prevented angiogenesis, decreased vascular endothelial growth factor-α, and was associated with a sustained increase in M1, M2a, and M2c markers after MI., Conclusions: Changes in angiogenesis and macrophage phenotype-related gene expression after MI are important for the fetal regenerative response to MI and are mediated at least in part by cardiac progenitor cells recruitment., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Fetal growth restriction (FGR) affects 7-10% pregnancies. Conventional and tissue Doppler imaging has noted cardiac compromise during fetal and early neonatal periods in this cohort. In this article, we discuss the use of salient ultrasound parameters across age groups. During fetal life, certain feto-placental sonographic parameters have been linked to adverse perinatal outcomes and are predictive of later life hypertension. During the early postnatal period altered morphometry (hypertrophied and globular hearts) with sub-clinical impairment of cardiac function has been noted in both term and preterm infants with FGR. Vascular imaging has noted thickened and stiffer arteries in association with significantly elevated blood pressure. Similar findings in the pediatric age groups indicate persistence of these alterations, and have formed the basis of intervention studies. Assessment methodology and clinical relevance of these parameters, especially in designing and monitoring of intervention strategies is discussed. Frontline care givers (obstetricians and neonatologists) are increasingly using point of care ultrasound to discern these manifestations of FGR during the sub-clinical phase.

Background: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging has enabled the accurate assessment of myocardial infarction (MI). However, LGE CMR has not been performed successfully in the fetus, where it could be useful for animal studies of interventions to promote cardiac regeneration. We believe that LGE imaging could allow us to document the presence, extent and effect of MI in utero and would thereby expand our capacity for conducting fetal sheep MI research. We therefore aimed to investigate the feasibility of using LGE to detect MI in sheep fetuses., Methods: Six sheep fetuses underwent a thoracotomy and ligation of a left anterior descending (LAD) coronary artery branch; while two fetuses underwent a sham surgery. LGE CMR was performed in a subset of fetuses immediately after the surgery and three days later. Early gadolinium enhancement (EGE) CMR was also performed in a subset of fetuses on both days. Cine imaging of the heart was performed to measure ventricular function., Results: The imaging performed immediately after LAD ligation revealed no evidence of infarct on LGE (n=3). Two of four infarcted fetuses (50%) showed hypoenhancement at the infarct site on the EGE images. Three days after the ligation, LGE images revealed a clear, hyper-enhanced infarct zone in four of the five infarcted fetuses (80%). No hyper-enhanced infarct zone was seen on the one sham fetus that underwent LGE CMR. No hypoenhancement could be seen in the EGE images in either the sham (n=1) or the infarcted fetus (n=1). No regional wall motion abnormalities were apparent in two of the five infarcted fetuses., Conclusion: LGE CMR detected the MI three days after LAD ligation, but not immediately after. Using available methods, EGE imaging was less useful for detecting deficits in perfusion. Our study provides evidence for the ability of a non-invasive tool to monitor the progression of cardiac repair and damage in fetuses with MI. However, further investigation into the optimal timing of LGE and EGE scans and improvement of the sequences should be pursued with the aim of expanding our capacity to monitor cardiac regeneration after MI in fetal sheep.

The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast component. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two complementary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro-associated noncoding Y ssRNA. The top 10 upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response [e.g., IFN-induced protein 44-like (IFI44L), of MX dynamin-like GTPase (MX)1, MX2, and radical S -adenosyl methionine domain containing 2 (Rsad2)]. Within the fibrotic pathway, transcript levels of endothelin-1 (EDN1), phosphodiesterase (PDE)4D, chemokine (C-X-C motif) ligand (CXCL)2, and CXCL3 were upregulated, while others, including adenomedullin, RAP guanine nucleotide exchange factor 3 (RAPGEF3), tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, and dual specificity phosphatase 1, were downregulated. Agnostic Database for Annotation, Visualization and Integrated Discovery analysis revealed a significant increase in inflammatory genes, including complement C3A receptor 1 (C3AR1), F2R-like thrombin/trypsin receptor 3, and neutrophil cytosolic factor 2. In addition, stimulated fibroblasts expressed high levels of phospho-MADS box transcription enhancer factor 2 [a substrate of MAPK5 (ERK5)], which was inhibited by BIX-02189, a specific inhibitor of ERK5. Translation to human disease leveraged an unprecedented opportunity to interrogate the transcriptome of fibroblasts freshly isolated and cell sorted without stimulation from a fetal heart with CHB and a matched healthy heart. Consistent with the in vitro data, five IFN response genes were among the top 10 most highly expressed transcripts in CHB fibroblasts. In addition, the expression of matrix-related genes reflected fibrosis. These data support the novel finding that cardiac injury in CHB may occur secondary to abnormal remodeling due in part to upregulation of type 1 IFN response genes. NEW & NOTEWORTHY Congenital heart block is a rare disease of the fetal heart associated with maternal anti-Ro autoantibodies which can result in death and for survivors, lifelong pacing. This study provides in vivo and in vitro transcriptome-support that injury may be mediated by an effect of Type I Interferon on fetal fibroblasts., (Copyright © 2017 the American Physiological Society.)

It is currently recommended that hydroxychloroquine (HCQ) be maintained during pregnancy in patients with systemic lupus erythematosus. Recent data suggest that this Toll-like receptor inhibitor may also reduce the recurrence rate of anti-SSA/Ro associated congenital heart block (CHB). This case report describes a unique situation in which a CHB-afflicted, HCQ-exposed pregnancy was electively terminated. The heart did not reveal any characteristic features of cardiotoxicity, providing further evidence supporting the safety of foetal exposure to HCQ.

Background: Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth., Methods and Results: We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling., Conclusions: Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Accurate prenatal diagnosis of complex congenital cardiovascular anomalies, vascular ones in particular, is still challenging. A fetal cardiovascular cast model can provide a copy of the cardiac chambers and great vessels with normal or pathological structures. This study was aimed to demonstrate three-dimensional anatomy of complex congenital cardiovascular anomalies in fetuses by means of corrosion casting. Twenty fetuses with prenatal-ultrasound-diagnosed complex cardiovascular anomalies were enrolled in this study (19 to 35 gestational weeks). Fetal cardiovascular cast models were made by a corrosion casting technique. The specimens were injected with casting material via the umbilical vein, and then immersed in strong acid after casting fluid was solidified, to disclose the geometries of cardiovascular cavities. Nineteen cast models were successfully made from 20 specimens. The casts distinctly showed the morphological malformations and spatial relationship between cardiac chambers and great vessels. One hundred and eleven abnormalities were revealed by casting in the 19 specimens, including 34 abnormalities located in the cardiac chambers (3, 4 and 27 anomalies in the atria, atrioventricular valves and ventricles, respectively), and 77 in the great vessels (28, 20, 24 and 5 anomalies in the aorta and its branches, the pulmonary artery, the ductus arteriosus and the major veins, respectively). Corrosion casting can display three-dimensional anatomy of fetal complex cardiovascular anomalies. This improves our understanding of related pathomorphology and prenatal diagnosis.

Tetralogy of fallot (TOF) is one of the most prevalent types of congenital heart diseases. As a category of bioactive molecules, peptides have been proved to participate in various biological processes. However, the role of endogenous peptides in the pathogenesis of TOF has not been studied. In this study, we performed a comparative peptidomic profile in the fetal heart of TOF and the control group for the first time by liquid chromatography-tandem mass spectrometry. Our data demonstrated that a total of 201 peptides derived from 176 precursor proteins were differentially expressed in the heart tissues of TOF fetuses compared with normal controls, including 41 upregulated peptides and 160 downregulated peptides. After analyzing the characteristics of these differentially expressed peptides and their precursor proteins, we found that these peptides were potentially involved in different biological processes, especially cardiogenesis and congenital anomaly of the cardiovascular system. Interestingly, we detected several extracellular matrix-derived peptides involved in our differentially expressed peptidomic profile. In summary, our study constructed a comparative peptidomic profile from the heart tissues of TOF fetuses and normal controls, and it identified a series of peptides that could potentially participate in heart development and TOF formation. The emergence of our peptidomics study indicated a new perspective to explore the pathogenesis of abnormal heart morphology, especially TOF.