Publications by authors named "Mike Seed"

119 Publications

Normative Data for Myocardial Native T1 and Extracellular Volume Fraction in Children.

Radiol Cardiothorac Imaging 2020 Aug 13;2(4):e190234. Epub 2020 Aug 13.

Department of Pediatrics, Division of Cardiology, Stollery Children's Hospital, University of Alberta, Edmonton, Canada (J.J.P.); Department of Paediatrics, Division of Cardiology (D.Y., S.J.Y., M.S., L.G.W.) and Department of Diagnostic Imaging (C.Z.L., S.J.Y., M.S., L.G.W.), The Hospital for Sick Children, University of Toronto, Toronto, Canada; and Department of Cardiology, Princess Margaret Hospital for Children, Perth, Australia (D.Y.).

Purpose: To establish normative data for myocardial T1, including extracellular volume (ECV) fraction, in healthy children.

Materials And Methods: In this retrospective, single-center study, T1 mapping data were collected from 48 healthy pediatric patients (14 years ± 3 [standard deviation]; range, 9-18 years; 27 of 48 [56%] male) referred for cardiac screening 1.5-T MRI between 2014 and 2017. T1 relaxometry was performed using a 5(number of heartbeats [nHB])3 modified Look-Locker inversion recovery (MOLLI) sequence, where nHB was three to five heartbeats depending on the heart rate, and was repeated 15 minutes following the administration of 0.2 mmol per kilogram of body weight of gadobenate dimeglumine, with 19 patients receiving contrast material. T1 values were calculated using a curve-fitting algorithm on average region-of-interest signal and corrected for imperfect inversion pulse efficiency. Comparisons within patients were performed with paired Student test, between groups with unpaired Student test or Mann-Whitney test, and linear regression was performed to examine for associations with other variables.

Results: Average native T1 was 1008 msec ± 31, with a nonsignificant increase in females (1017 msec ± 27 vs 1001 msec ± 33, = .066). Average ECV was 20.8% ± 2.4, with a nonsignificant increase in values in females (21.7% ± 1.9 vs 20.0% ± 2.6, = .123). T1 and ECV values were increased in the septum versus the free wall.

Conclusion: Normative data are presented for myocardial native T1 and ECV using the MOLLI T1 mapping sequence at 1.5 T.© RSNA, 2020.
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http://dx.doi.org/10.1148/ryct.2020190234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977704PMC
August 2020

Haemodynamics and cerebral oxygenation of neonatal piglets in the immediate ex utero period supported by mechanical ventilation or ex utero oxygenator.

J Physiol 2021 Mar 21. Epub 2021 Mar 21.

Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

Key Points: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator-induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air-breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post-oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT). Post-transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets. The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post-transition period.

Abstract: Gestational age at birth is a major predictor of wellbeing; the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability (<24 weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm-associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post-transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO ) decreased from in utero levels post-transition; however, cerebral regional oxygen saturation (rSO ) was maintained at fetal-like levels. OXY piglets became hypoxaemic and retained CO . Whether OXY piglets are able to maintain cerebral rSO under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow.
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http://dx.doi.org/10.1113/JP280803DOI Listing
March 2021

Usefulness of TI-scout images in the assessment of late gadolinium enhancement in children.

J Cardiovasc Magn Reson 2021 Mar 18;23(1):28. Epub 2021 Mar 18.

Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada.

Background: Cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) requires identification of the normal myocardial nulling time using inversion time (TI)-scout imaging sequence. Although TI-scout images are not primarily used for myocardial assessment, they provide information regarding different signal recovery patterns of normal and abnormal myocardium facilitating identification of LGE in instances where standard LGE images alone are not diagnostic. We aimed to assess the diagnostic performance of TI-scout as compared to that of standard LGE images.

Methods: CMR studies with LGE imaging in 519 patients (345 males, 1-17 years) were reviewed to assess the diagnostic performance of LGE imaging in terms of the location of LGE and the pathologic entities. The diagnostic performance of the TI-scout and standard LGE imaging was classified into four categories: (1) equally diagnostic, (2) TI-scout superior to standard LGE, (3) standard LGE superior to TI-scout, and (4) complementary, by the consensus of the two observers.

Results: The study cohort consisted of 440 patients with negative LGE and 79 with evidence for LGE. For a negative diagnosis of LGE, TI-scout and standard LGE images were equally diagnostic in 75% of the cases and were complementary in 12%. For patients with LGE, TI-scout images were superior to standard LGE images in 52% of the cases and were complementary in 19%. The diagnostic performance of TI-scout images was superior to that of standard LGE images in all locations. TI-scout images were superior to standard LGE images in 11 of 12 (92%) cases with LGE involving the papillary muscles, in 7 /12 (58%) cases with subendocardial LGE, and in 4/7 (57%) cases with transmural LGE. TI-scout images were particularly useful assessing the presence and extent of LGE in hypertrophic cardiomyopathy (HCM). TI-scout was superior to standard LGE in 6/10 (60%) and was complementary in 3/10 (30%) of the positive cases with HCM.

Conclusions: TI-scout images enhance the diagnostic performance of LGE imaging in children.
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http://dx.doi.org/10.1186/s12968-021-00719-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972209PMC
March 2021

Myocardial Fibrosis in Pediatric Patients With Ebstein's Anomaly.

Circ Cardiovasc Imaging 2021 Mar 16:CIRCIMAGING120011136. Epub 2021 Mar 16.

Division of Cardiology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada. (S.A., M.S., L.G.-W.).

Background: Left ventricular dysfunction in Ebstein's anomaly (EA) is associated with higher mortality. The health of the left ventricular myocardium in children and adolescents with EA has not been investigated in detail.

Methods: Patients with unrepaired EA who had undergone cardiac magnetic resonance imaging including T1 mapping were retrospectively reviewed. Patients were compared with age- and sex-matched controls. EA severity index was calculated using volumetric measurements at end diastole ([right atrial+atrialized right ventricular volumes]/[functional right ventricular+left atrial+left ventricular volumes]). Global circumferential and radial strain and as well as strain rate were examined using cardiac magnetic resonance feature tracking.

Results: Twelve EA patients and an equal number of controls were included. Functional and atrialized right ventricular end-diastolic volumes were 84±15 and 21±13 mL/m, respectively. Late gadolinium enhancement, confined to the right ventricle, was found in 2 patients (16%). Left ventricular native T1 values and extracellular volume fractions were higher in patients compared with controls (1026±47 versus 956±40 ms, =0.0004 and 28.5±3.4% versus 22.5±2.6%, <0.001, respectively). Native T1 times correlated inversely with patients' age, body surface area, and O saturations (r=-0.63, -0.62, and -0.91, respectively; =0.02, =0.02, and <0.0001, respectively). EA severity index ranged between 0.15 and 0.94 and correlated with T1 values (r=0.76, =0.003). Native T1 correlated with global circumferential strain (r=0.58, =0.04) but not ejection fraction (EF). EA patients had reduced maximum oxygen uptake (Vomax). Vomax correlated inversely with T1 values (r=-0.79, =0.01).

Conclusions: Children and adolescents with EA experience an abnormal degree of diffuse myocardial fibrosis. Its association with O saturation points toward a role of hypoxemia in the pathogenesis of fibrosis. Larger and prospective studies are needed to evaluate the value of T1 mapping for risk stratification and monitoring in EA.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011136DOI Listing
March 2021

An MRI approach to assess placental function in healthy humans and sheep.

J Physiol 2021 Mar 6. Epub 2021 Mar 6.

Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Key Points: Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental by MRI was ∼4 ml min  kg fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential.

Abstract: It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( ) and in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal and . Maternal (ml min  kg fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal (ml min  kg fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min  kg fetus) decreased with advancing age (P = 0.008), while fetal was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal was preserved through stable umbilical flow (ml min  kg ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'.
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http://dx.doi.org/10.1113/JP281002DOI Listing
March 2021

Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus.

Physiol Rep 2021 Mar;9(5):e14742

Division of Cardiovascular Surgery, The Labatt Family Heart Centre, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Artificial placenta (AP) technology aims to maintain fetal circulation, while promoting the physiologic development of organs. Recent reports of experiments performed in sheep indicate the intrauterine environment can be recreated through the cannulation of umbilical vessels, replacement of the placenta with a low-resistance membrane oxygenator, and incubation of the fetus in fluid. However, it remains to be seen whether animal fetuses similar in size to the extremely preterm human infant that have been proposed as a potential target for this technology can be supported in this way. Preterm Yucatan miniature piglets are similar in size to extremely preterm human infants and share similar umbilical cord anatomy, raising the possibility to serve as a good model to investigate the AP. To characterize fetal cardiovascular physiology, the carotid artery (n = 24) was cannulated in utero and umbilical vein (UV) and umbilical artery were sampled. Fetal UV flow was measured by MRI (n = 16). Piglets were delivered at 98 ± 4 days gestation (term = 115 days), cannulated, and supported on the AP (n = 12) for 684 ± 228 min (range 195-3077 min). UV flow was subphysiologic (p = .002), while heart rate was elevated on the AP compared with in utero controls (p = .0007). We observed an inverse relationship between heart rate and UV flow (r = .4527; p < .001) with progressive right ventricular enlargement that was associated with reduced contractility and ultimately hydrops and circulatory collapse. We attribute this to excessive afterload imposed by supraphysiologic circuit resistance and augmented sympathetic activity. We conclude that short-term support of the preterm piglet on the AP is feasible, although we have not been able to attain normal fetal physiology. In the future, we propose to investigate the feasibility of an AP circuit that incorporates a centrifugal pump in our miniature pig model.
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http://dx.doi.org/10.14814/phy2.14742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923578PMC
March 2021

A Life-Course Approach to the Neurodevelopmental Trajectory of Congenital Heart Disease.

Circulation 2021 Mar 1;143(9):892-894. Epub 2021 Mar 1.

Department of Paediatrics, Hospital for Sick Children and The University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052436DOI Listing
March 2021

3D Modeling and Printing in Congenital Heart Surgery: Entering the Stage of Maturation.

Front Pediatr 2021 5;9:621672. Epub 2021 Feb 5.

Department of Surgery-Division of Cardiovascular Surgery, Hospital for Sick Children, The University of Toronto, Toronto, ON, Canada.

3D printing allows the most realistic perception of the surgical anatomy of congenital heart diseases without the requirement of physical devices such as a computer screen or virtual headset. It is useful for surgical decision making and simulation, hands-on surgical training (HOST) and cardiovascular morphology teaching. 3D-printed models allow easy understanding of surgical morphology and preoperative surgical simulation. The most common indications for its clinical use include complex forms of double outlet right ventricle and transposition of the great arteries, anomalous systemic and pulmonary venous connections, and heterotaxy. Its utility in congenital heart surgery is indisputable, although it is hard to "scientifically" prove the impact of its use in surgery because of many confounding factors that contribute to the surgical outcome. 3D-printed models are valuable resources for morphology teaching. Educational models can be produced for almost all different variations of congenital heart diseases, and replicated in any number. HOST using 3D-printed models enables efficient education of surgeons in-training. Implementation of the HOST courses in congenital heart surgical training programs is not an option but an absolute necessity. In conclusion, 3D printing is entering the stage of maturation in its use for congenital heart surgery. It is now time for imagers and surgeons to find how to effectively utilize 3D printing and how to improve the quality of the products for improved patient outcomes and impact of education and training.
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http://dx.doi.org/10.3389/fped.2021.621672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892770PMC
February 2021

Impact of resveratrol-mediated increase in uterine artery blood flow on fetal haemodynamics, blood pressure and oxygenation in sheep.

Exp Physiol 2021 Feb 18. Epub 2021 Feb 18.

Early Origins of Adult Health Research Group, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

New Findings: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised.

Abstract: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123-124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted.
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http://dx.doi.org/10.1113/EP089237DOI Listing
February 2021

Prevalence, Risk Factors, and Impact of Preoperative Seizures in Neonates With Congenital Heart Disease.

J Clin Neurophysiol 2021 Feb 4. Epub 2021 Feb 4.

Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Division of Paediatric Neurology, Department of Paediatrics, Geneva University Hospital, Geneva, Switzerland; Division of Cardiology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; and Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Purpose: The purpose of this study was to assess the prevalence, risk factors, and impact of electrographic seizures in neonates with complex congenital heart disease before cardiac surgery.

Methods: A cohort of 31 neonates with congenital heart disease monitored preoperatively with continuous video-EEG (cEEG) was first reviewed for electrographic seizure burden and EEG background abnormalities. Second, cEEG findings were correlated with brain MRI and 18-month outcomes.

Results: Continuous video-EEG was recorded preoperatively for a median duration of 20.5 hours (range, 2.5-93.5 hours). The five neonates (16%; 95% confidence interval, 5.5% to 34%) with seizures detected on cEEG in the preoperative period had a diagnosis of transposition of the great arteries or similar physiology, detected in four of five postnatally. None of the 157 recorded electrographic seizures had a clinical correlate. The median time to first seizure was 65 minutes (range, 6-300 minutes) after cEEG hookup. The median maximum hourly seizure burden was 12.4 minutes (range, 7-23 minutes). Before the first electrographic seizure, a prolonged interburst interval (>10 seconds) was not associated with seizures (coefficient 1.2; 95% confidence interval, -1.1 to 3.6). MRI brain lesions were three times more common in neonates with seizures. Sharp wave transients on cEEG were associated with delayed opercular development.

Conclusions: In this cohort, preoperative electrographic seizures were common, were all subclinical, and were associated with MRI brain injury and postnatal diagnosis of transposition of the great arteries. The findings motivate further study of the mechanisms of preoperative brain injury, particularly among neonates with a postnatal diagnosis of transposition of the great arteries.
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http://dx.doi.org/10.1097/WNP.0000000000000825DOI Listing
February 2021

Human Fetal Blood Flow Quantification with Magnetic Resonance Imaging and Motion Compensation.

J Vis Exp 2021 01 7(167). Epub 2021 Jan 7.

Department of Medical Biophysics, University of Toronto; Division of Translational Medicine, The Hospital for Sick Children;

Magnetic resonance imaging (MRI) is an important tool for the clinical assessment of cardiovascular morphology and heart function. It is also the recognized standard-of-care for blood flow quantification based on phase contrast MRI. While such measurement of blood flow has been possible in adults for decades, methods to extend this capability to fetal blood flow have only recently been developed. Fetal blood flow quantification in major vessels is important for monitoring fetal pathologies such as congenital heart disease (CHD) and fetal growth restriction (FGR). CHD causes alterations in the cardiac structure and vasculature that change the course of blood in the fetus. In FGR, the path of blood flow is altered through the dilation of shunts such that the oxygenated blood supply to the brain is increased. Blood flow quantification enables assessment of the severity of the fetal pathology, which in turn allows for suitable in utero patient management and planning for postnatal care. The primary challenges of applying phase contrast MRI to the human fetus include small blood vessel size, high fetal heart rate, potential MRI data corruption due to maternal respiration, unpredictable fetal movements, and lack of conventional cardiac gating methods to synchronize data acquisition. Here, we describe recent technical developments from our lab that have enabled the quantification of fetal blood flow using phase contrast MRI, including advances in accelerated imaging, motion compensation, and cardiac gating.
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http://dx.doi.org/10.3791/61953DOI Listing
January 2021

PPARγ activation in late gestation does not promote surfactant maturation in the fetal sheep lung.

J Dev Orig Health Dis 2021 Jan 7:1-12. Epub 2021 Jan 7.

Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.

Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ; Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ, surfactant proteins (SFTP-A, -B, -C, and -D), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1. Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B. However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.
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http://dx.doi.org/10.1017/S204017442000135XDOI Listing
January 2021

Fetal cardiovascular magnetic resonance imaging.

Pediatr Radiol 2020 12 30;50(13):1881-1894. Epub 2020 Nov 30.

The Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada.

Fetal cardiovascular MRI is showing promise as a clinical diagnostic tool in the setting of congenital heart disease when the cardiac anatomy is unresolved by US or when complementary quantitative data on blood flow, oxygen saturation and hematocrit are required to aid in management. Compared with postnatal cardiovascular MRI, prenatal cardiovascular MRI still has some technical limitations. However, ongoing technical advances continue to improve the robustness and usability of fetal cardiovascular MRI. In this review, we provide an overview of the state of the art of fetal cardiovascular MRI and summarize the current focus of clinical application for this versatile technique.
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http://dx.doi.org/10.1007/s00247-020-04902-yDOI Listing
December 2020

Fetal brain growth and risk of postnatal white matter injury in critical congenital heart disease.

J Thorac Cardiovasc Surg 2020 Oct 1. Epub 2020 Oct 1.

Department of Pediatrics, University of Toronto Hospital for Sick Children, Toronto, Ontario, Canada.

Objective: To test the hypothesis that delayed brain development in fetuses with d-transposition of the great arteries or hypoplastic left heart syndrome heightens their postnatal susceptibility to acquired white matter injury.

Methods: This is a cohort study across 3 sites. Subjects underwent fetal (third trimester) and neonatal preoperative magnetic resonance imaging of the brain to measure total brain volume as a measure of brain maturity and the presence of acquired white matter injury after birth. White matter injury was categorized as no-mild or moderate-severe based on validated grading criteria. Comparisons were made between the injury groups.

Results: A total of 63 subjects were enrolled (d-transposition of the great arteries: 37; hypoplastic left heart syndrome: 26). White matter injury was present in 32.4% (n = 12) of d-transposition of the great arteries and 34.6% (n = 8) of those with hypoplastic left heart syndrome. Overall total brain volume (taking into account fetal and neonatal scan) was significantly lower in those with postnatal moderate-severe white matter injury compared with no-mild white matter injury after adjusting for age at scan and site in d-transposition of the great arteries (coefficient: 14.8 mL, 95% confidence interval, -28.8 to -0.73, P = .04). The rate of change in total brain volume from fetal to postnatal life did not differ by injury group. In hypoplastic left heart syndrome, no association was noted between overall total brain volume and change in total brain volume with postnatal white matter injury.

Conclusions: Lower total brain volume beginning in late gestation is associated with increased risk of postnatal moderate-severe white matter injury in d-transposition of the great arteries but not hypoplastic left heart syndrome. Rate of brain growth was not a risk factor for white matter injury. The underlying fetal and perinatal physiology has different implications for postnatal risk of white matter injury.
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http://dx.doi.org/10.1016/j.jtcvs.2020.09.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012393PMC
October 2020

Systematic Approach to Malalignment Type Ventricular Septal Defects.

J Am Heart Assoc 2020 11 10;9(22):e018275. Epub 2020 Nov 10.

The Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario Canada.

Various congenital heart diseases are associated with malalignment of a part of the ventricular septum. Most commonly, the outlet septum is malaligned toward the right or left ventricle. Less commonly, the whole or a major part of the ventricular septum is malaligned in relation to the atrial septal plane. Although the pathological conditions associated with ventricular septal malalignment have been well recognized, the descriptions are often confusing and sometimes incorrect. In this pictorial essay, we introduce our systematic approach to the assessment of malalignment type ventricular septal defects with typical case examples. The systematic approach comprises description of the essential features of malalignment, including the following: (1) the malaligned part of the ventricular septum, (2) the reference structure, (3) the mechanism of malalignment, (4) the direction of malalignment, and (5) the severity of malalignment.
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http://dx.doi.org/10.1161/JAHA.120.018275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763733PMC
November 2020

Fetal Flow Quantification in Great Vessels Using Motion-Corrected Radial Phase Contrast MRI: Comparison With Cartesian.

J Magn Reson Imaging 2021 02 20;53(2):540-551. Epub 2020 Aug 20.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Background: Phase contrast MRI in the great vessels is a potential clinical tool for managing fetal pathologies. One challenge is the uncontrollable fetal motion, potentially corrupting flow quantifications.

Purpose: To demonstrate improvements in fetal blood flow quantification in great vessels using retrospectively motion-corrected golden-angle radial phase contrast MRI relative to Cartesian phase contrast MRI.

Study Type: Method comparison.

Phantom/subjects: Computer simulation. Seventeen pregnant volunteers.

Field Strength/sequence: 1.5T and 3T. Cartesian and golden-angle radial phase contrast MRI.

Assessment: Through computer simulations, radial (with and without retrospective motion correction) and Cartesian phase contrast MRI were compared using flow deviations. in vivo Cartesian and radial phase contrast MRI measurements and reconstruction qualities were compared in pregnancies. Cartesian data were reconstructed into gated reconstructions (CINEs) after cardiac gating with metric optimized gating (MOG). For radial data, real-time reconstructions were performed for motion correction and MOG followed by CINE reconstructions.

Statistical Tests: Wilcoxon signed-rank test. Linear regression. Bland-Altman plots. Student's t-test.

Results: Simulations showed significant improvements (P < 0.05) in flow accuracy and reconstruction quality with motion correction ([mean/peak] flow errors with ±5 mm motion corruption: Cartesian [35 ± 1/115 ± 7] mL/s, motion uncorrected radial [25 ± 1/75 ± 2] mL/s and motion-corrected radial [1.0 ± 0.5/-5 ± 1] mL/s). in vivo Cartesian reconstructions without motion correction had lower quality than the motion-corrected radial reconstructions (P < 0.05). Across all fetal mean flow measurements, the bias [limits of agreement] between the two measurements were -0.2 [-76, 75] mL/min/kg, while the linear regression coefficients were (M = 0.81 × M + 29.8 [mL/min/kg], r = 0.67). The corresponding measures for the peak fetal flows were -23 [-214, 167] mL/min/kg and (P = 0.95 × P -1.2 [mL/min/kg], r = 0.80). Cartesian reconstructions of low quality showed significantly higher estimated mean and peak (P < 0.05) flows than the corresponding radial reconstructions.

Data Conclusion: Simulations showed that radial phase contrast MRI with motion compensation improved flow accuracy. For fetal measurements, motion-corrected radial reconstructions showed better image quality than, and different flow values from, Cartesian reconstructions. Level of Evidence 1. Technical Efficacy Stage 1. J. MAGN. RESON. IMAGING 2021;53:540-551.
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http://dx.doi.org/10.1002/jmri.27334DOI Listing
February 2021

Umbilical vein infusion of prostaglandin I increases ductus venosus shunting of oxygen-rich blood but does not increase cerebral oxygen delivery in the fetal sheep.

J Physiol 2020 11 23;598(21):4957-4967. Epub 2020 Aug 23.

Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia.

Key Points: The ductus venosus (DV) is a dynamic fetal shunt that allows substrate-rich blood from the umbilical vein to bypass the hepatic circulation. In vitro studies suggest a direct role of prostaglandin I (PGI ) in the regulation of DV tone; however, the extent of this regulation has not been determined in utero. 4D flow and T oximetry magnetic resonance imaging can be combined to determine blood flow and oxygen delivery within the fetal circulation. PGI increases DV shunting of substrate-rich blood but this does not increase cerebral oxygen delivery.

Abstract: During fetal development, the maintenance of adequate oxygen and nutrient supply to vital organs is regulated through specialized fetal shunts. One of these shunts, the ductus venosus (DV), allows oxygen-rich blood to preferentially stream from the placenta toward the heart and brain. Herein, we combine magnetic resonance imaging (MRI) techniques that measure blood flow (4D flow) and oxygen saturation (T oximetry) in the fetal circuit to determine whether umbilical vein infusion of prostaglandin I (PGI , regulator of DV tone ex utero) directly dilates the DV and thus increases the preferential streaming of oxygen-rich blood toward the brain. At 114-115 days gestational age (dGA; term = 150 days), fetal sheep (n = 6) underwent surgery to implant vascular catheters in the fetal femoral artery, femoral vein, amniotic cavity and umbilical vein. Fetal MRI scans were performed at 119-124 dGA. 4D flow and T oximetry were performed to measure blood flow and oxygen saturation across the fetal circulation in both a basal state and whilst the fetus was receiving a continuous infusion of PGI . The proportion of oxygenated blood that passed through the DV from the umbilical vein was increased by PGI . Cerebral oxygen delivery was unchanged in the PGI state. This may be a result of decreased flow from the right to left side of the heart as blood flow through the foramen ovale was decreased by PGI . We have shown that although PGI acts on the DV to increase the proportion of oxygen-rich blood that bypasses the liver, this does not increase cerebral oxygen delivery in the fetal sheep.
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http://dx.doi.org/10.1113/JP280019DOI Listing
November 2020

Negative Impact of Obesity on Ventricular Size and Function and Exercise Performance in Children and Adolescents With Repaired Tetralogy of Fallot.

Can J Cardiol 2020 Sep 29;36(9):1482-1490. Epub 2020 Jun 29.

Division of Cardiology, Department of Pediatrics, University of Toronto, Labatt Family Heart Centre, Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address:

Background: Up to 25% of children with congenital heart disease are obese, which may have negative physiologic consequences for patients with repaired tetralogy of Fallot (rTOF).

Methods: Patients with rTOF who underwent cardiac magnetic resonance (CMR) imaging and cardiopulmonary exercise testing from 2007 to 2018 were reviewed. Complex rTOF patients were excluded. Obese patients (body mass index [BMI] ≥ 95th percentile) were compared with normal-weight patients (BMI < 85th percentile). CMR data were indexed to actual body surface area (aBSA), height, and BSA assuming ideal body weight (iBSA).

Results: We compared 32 obese patients matched with 64 normal-weight patients. Obese vs normal-weight patients had significantly lower right (RV; median 45% [interquartile range 42%-48%] vs 52% [47%-55%]; P < 0.0001) and left (LV; 52% [47%-56%] vs 56% [54%-60%]; P < 0.0001) ventricular ejection fractions (EFs). There were no statistically significant differences regarding aBSA-indexed volumes of the RV or LV at either end-diastole (EDV) or end-systole (ESV). However, when indexed to either height or iBSA, obese patients had significantly greater RVEDV and LVEDV, greater LV mass, and higher RV and LV stroke volumes. Obese patients had lower peak oxygen consumption and oxygen consumption at anaerobic threshold. These results did not change after adjusting for degree of pulmonary regurgitation.

Conclusions: Obesity is associated with increased biventricular size, decreased biventricular EFs, and impaired exercise performance after rTOF. These data suggest a potential role for cardiac rehabilitation for weight management and to optimize fitness.
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http://dx.doi.org/10.1016/j.cjca.2020.06.015DOI Listing
September 2020

Low preoperative superior vena cava blood flow predicts bidirectional cavopulmonary shunt failure.

J Thorac Cardiovasc Surg 2020 Dec 5;160(6):1529-1540.e4. Epub 2020 May 5.

Division of Cardiovascular Surgery, The Labatt Family Heart Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: In this study we sought to determine whether preoperative superior vena cava (SVC) blood flow measured using cardiac magnetic resonance (CMR) predicts physiology and clinical outcome after bidirectional cavopulmonary shunt (BCPS).

Methods: The retrospective single-center study included 65 (2012-2017) patients who underwent BCPS. Preoperative CMR imaging, echocardiography, catheterization, and clinical outcomes were reviewed. SVC flow was measured using phase contrast CMR. The Kaplan-Meier method and Cox regression was used for BCPS takedown-free survival and predictor analyses.

Results: The absolute and indexed SVC flow was 0.5 (interquartile range [IQR], 0.4-0.7) L/min and 1.7 (IQR, 1.4-2.0) L/min/mm respectively, which was comparable with the SVC blood flow volume previously measured. The median age and body weight at BCPS was 6.5 (IQR, 5.5-8.5) months and 6.9 (IQR, 6.0-7.7) kg. After follow-up, at a median of 17.1 (IQR, 7.9-41.3) months, 14 patients (21.5%) underwent the Fontan completion and 40 (61.5%) with BCPS physiology were waiting for the Fontan completion. The 11 remaining patients (16.9%), included those who underwent takedown (n = 7; 10.8%) or died with a BCPS (n = 4; 6.2%). Severe hypoxia was the leading cause of mortality, directly accounting for two-thirds of deaths (66.6%; 6/9). The BCPS takedown-free survival was 96.8% at 6 months, and 79.9% at 3 years. Preoperative SVC blood flow was significantly positively correlated with early post-BCPS arterial saturation (P = .00). The multivariable analysis showed SVC flow was the only factor associated with BCPS failure (hazard ratio, 0.186; P = .04) among the predictors related to the pre-BCPS anatomy and physiology.

Conclusions: SVC blood flow might be as critically important as pulmonary artery anatomic and physiologic parameters in the evaluation of BCPS candidacy in the single-ventricle population.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.098DOI Listing
December 2020

Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts.

Front Physiol 2020 10;11:614. Epub 2020 Jun 10.

Early Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, Australia.

Aims: Animal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart.

Methods: We used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI.

Results: 73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation.

Conclusion: There were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.
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http://dx.doi.org/10.3389/fphys.2020.00614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298149PMC
June 2020

Technique for comprehensive fetal hepatic blood flow assessment in sheep using 4D flow MRI.

J Physiol 2020 09 1;598(17):3555-3567. Epub 2020 Jul 1.

Translational Medicine, Hospital for Sick Children, Department of Medical Biophysics, University of Toronto.

Key Points: The comprehensive visualization and quantification of in vivo fetal hepatic haemodynamics, particularly the shunting of ductus venosus blood, has been elusive and is not yet fully understood. We introduce the combination of chronically instrumented fetal sheep and 4D flow MRI of the whole fetal liver, which allows retrospective blood flow measurement in all visible vessels as well as qualitative assessment. The applicability and usefulness of this technique is exhibited in normally grown fetal Merino sheep in mid- and late-gestation with detailed dynamic distribution of hepatic blood flow presented. The feasibility of this approach in clinical pathology is demonstrated in two growth-restricted fetuses at mid-gestation. Further exemplification of blood flow quantification is performed over major hepatic vessels.

Abstract: Although the fetal vasculature has been demarcated and well understood for several decades, the corresponding haemodynamics permitting oxygen- and nutrient-rich blood delivery to the fetal organs has been comparatively difficult to study. We married two well-established methods: 4D flow MRI, a volumetric and dynamic blood-flow measurement technique, and chronically instrumented sheep to broadly assess fetal hepatic circulation. We performed this technique in mid- and late-gestation fetal Merino sheep under normoxemic conditions and major hepatic vasculature was segmented to quantify blood flow and related parameters. Dynamic blood flow was visualized, exhibiting an acceleration of umbilical vein blood through the ductus venosus as well as spiralling into the inferior vena cava where its stream remained separate from that of the hepatic veins and lower body. Ductus venosus changes from mid- to late-gestation included larger diameter (mid: 5.8 ± 0.9 vs. late: 7.1 ± 1.1 mm; P = 0.003) and cross-sectional area (mid: 27.1 ± 8.6 vs. late: 40.4 ± 11.8 mm ; P = 0.003), and lower velocity averaged over the cardiac cycle (mid: 15.7 ± 5.4 vs. late: 9.8 ± 7.0 cm s ; P = 0.020). This resulted in higher magnitude blood flow (indexed to umbilical vein input) at mid-gestation in the ductus venosus (mid: 0.73 ± 0.21; late: 0.46 ± 0.21; P = 0.008). The visualization and quantification results support the further use of this technique to better understand regional blood flow changes during normal or abnormal fetal growth, as well as to observe acute haemodynamic responses to physiological challenges or drug interventions.
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http://dx.doi.org/10.1113/JP279631DOI Listing
September 2020

Feasibility of ventricular volumetry by cardiovascular MRI to assess cardiac function in the fetal sheep.

J Physiol 2020 07 2;598(13):2557-2573. Epub 2020 Jun 2.

Division of Cardiology, Hospital for Sick Children, Toronto, Canada.

Key Points: The application of fetal cardiovascular magnetic resonance imaging (CMR) to assess fetal cardiovascular physiology and cardiac function through the quantification of ventricular volumes has previously been investigated, but the approach has not yet been fully validated. Ventricular output measurements calculated from heart rate and stroke volumes (SV) of the right and left ventricles measured by ventricular volumetry (VV) exhibited a high level of agreement with phase-contrast (PC) blood flow measurements in the main pulmonary artery and ascending aorta, respectively. Ejection fraction of the right ventricle, which is lower than that of the left ventricle in postnatal subjects, was similar to the left ventricular ejection fraction in the fetus; probably due to the different loading conditions present in the fetal circulation. This study provides evidence to support the reliability of VV in the sheep fetus, providing evidence for its use in animal models of human diseases affecting the fetal circulation.

Abstract: The application of ventricular volumetry (VV) by cardiovascular magnetic resonance imaging (CMR) in the fetus remains challenging due to the small size of the fetal heart and high heart rate. The reliability of this technique in utero has not yet been established. The aim of this study was to assess the feasibility and reliability of VV in a fetal sheep model of human pregnancy. Right and left ventricular outputs by stroke volume (SV) measured using VV were compared with 2D phase-contrast (PC) CMR measurements of blood flow in the main pulmonary artery (MPA) and ascending aorta (AAo). At 124-140 days (d) gestation, singleton bearing Merino ewes underwent CMR under general anaesthesia using fetal femoral artery catheters, implanted at 109-117d, to trigger cine steady state free precession acquisitions of ventricular short-axis stacks. The short-axis cine stacks were segmented at end-systole and end-diastole, yielding right and left ventricular SV, ejection fraction, and cardiac outputs (SV × heart rate). PC cine acquisitions of MPA and AAo were analysed to measure blood flow, which served as comparators for the right and left cardiac outputs by VV. There was good correlation and agreement between VV and PC measures of ventricular outputs with no significant bias (r  = 0.926; P < 0.0001; Bias = -4.7 ± 10.5 ml min  kg ; 95% limits of agreement: -15.9 to 25.2 ml min  kg ). This study validates fetal VV by CMR in a large animal model of human pregnancy and provides preliminary reference values of fetal sheep right and left ventricles in late gestation.
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http://dx.doi.org/10.1113/JP279054DOI Listing
July 2020

Normal human and sheep fetal vessel oxygen saturations by T2 magnetic resonance imaging.

J Physiol 2020 08 29;598(15):3259-3281. Epub 2020 May 29.

Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.

Key Points: Human fetal Doppler ultrasound and invasive blood gas measurements obtained by cordocentesis or at the time of delivery reveal similarities with sheep (an extensively used model for human fetal cardiovascular physiology). Oxygen saturation (SO ) measurements in human fetuses have been limited to the umbilical and scalp vessels, providing little information about normal regional SO differences in the fetus. Blood T2 MRI relaxometry presents a non-invasive measure of SO in the major fetal vessels. This study presents the first in vivo validation of fetal vessel T2 oximetry against the in vitro T2-SO relationship using catheterized sheep fetuses and compares the normal SO in the major vessels between the human and sheep fetal circulations. Human fetal vessel SO by T2 MRI confirms many similarities with the sheep fetal circulation and is able to demonstrate regional differences in SO ; in particular the significantly higher SO in the left versus right heart.

Abstract: Blood T2 magnetic resonance imaging (MRI) relaxometry non-invasively measures oxygen saturation (SO ) in major vessels but has not been validated in fetuses in vivo. We compared the blood T2-SO relationship in vitro (tubes) and in vivo (vessels) in sheep, and measured SO across the normal human and sheep fetal circulations by T2. Singleton pregnant ewes underwent surgery to implant vascular catheters. In vitro and in vivo sheep blood T2 measurements were related to corresponding SO measured using a blood gas analyser, as well as relating T2 and SO of human fetal blood in vitro. MRI oximetry was performed in the major vessels of 30 human fetuses at 36 weeks (term, 40 weeks) and 10 fetal sheep (125 days; term, 150 days). The fidelity of in vivo fetal T2 oximetry was confirmed through comparison of in vitro and in vivo sheep blood T2-SO relationships (P = 0.1). SO was similar between human and sheep fetuses, as was the fetal oxygen extraction fraction (human, 33 ± 11%; sheep, 34 ± 7%; P = 0.798). The presence of streaming in the human fetal circulation was demonstrated by the SO gradient between the ascending aorta (68 ± 10%) and the main pulmonary artery (49 ± 9%; P < 0.001). Human and sheep fetal vessel MRI oximetry based on T2 is a validated approach that confirms the presence of streaming of umbilical venous blood towards the heart and brain. Streaming is important in ensuring oxygen delivery to these organs and its disruption may have important implications for organ development, especially in conditions such as congenital heart disease and fetal growth restriction.
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http://dx.doi.org/10.1113/JP279725DOI Listing
August 2020

Decreased Brain Volumes and Infants With Congenital Heart Disease Undergoing Venoarterial Extracorporeal Membrane Oxygenation.

Pediatr Crit Care Med 2020 08;21(8):738-745

Department of Pediatrics (Neurology), The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.

Objectives: The aims of this study were to: i) determine the spectrum of brain injury and ii) compare brain volumes between pre- and postoperative brain MRI in the infants receiving extracorporeal membrane oxygenation compared with those who did not require extracorporeal membrane oxygenation.

Design: Cohort study of infants with D-transposition of the great arteries or single ventricle physiology. Brain volume (cm) was measured using a segmentation of a volumetric T1-weighted gradient echo sequence. Brain imaging findings (intraventricular hemorrhage, white matter injuries, and stroke) were analyzed with respect to known clinical risk factors for brain injury and adverse neurodevelopmental outcomes. Clinical factors were collected by retrospective chart review. The association between brain volume and extracorporeal membrane oxygenation was evaluated using generalized estimating equations to account for repeated measures.

Setting: Prospective and single-centered study.

Patients: One hundred nine infants (median gestational age, 39.1 wk) with D-transposition of the great arteries (n = 77) or single ventricle physiology (n = 32) were studied pre- and postoperatively with MRI as per clinical protocol.

Interventions: None.

Measurements And Main Results: Of the 28 infants (26%) receiving extracorporeal membrane oxygenation, 19 (68%) were supported with extracorporeal membrane oxygenation once, and nine (32%) were supported 2-4 times. On postoperative MRI, new white matter injury was found in only five (17%) of the extracorporeal membrane oxygenation infants versus 40 (49%) in the non-extracorporeal membrane oxygenation group (p = 0.073). The rate of stroke (9% vs 10%), intraventricular hemorrhage (24% vs 29%), and hypoxic ischemia (3% vs 14%) did not differ between the non-extracorporeal membrane oxygenation and extracorporeal membrane oxygenation groups (all p > 0.5). Accounting for D-transposition of the great arteries or single ventricle physiology diagnosis, infants requiring extracorporeal membrane oxygenation had slower brain volume with single (β = -1.67) or multiple extracorporeal membrane oxygenation runs ([β = -6.54]; overall interaction p = 0.012).

Conclusions: Patients with d-transposition of the great arteries or single ventricle physiology undergoing extracorporeal membrane oxygenation at our center have a similar incidence of brain injury but more significant impairment of perioperative brain volumes than those not requiring extracorporeal membrane oxygenation.
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http://dx.doi.org/10.1097/PCC.0000000000002336DOI Listing
August 2020

Understanding Fetal Hemodynamics Using Cardiovascular Magnetic Resonance Imaging.

Fetal Diagn Ther 2020 14;47(5):354-362. Epub 2020 Feb 14.

Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada,

Human fetal circulatory physiology has been investigated extensively using grey-scale ultrasound, which provides excellent visualization of cardiac anatomy and function, while velocity profiles in the heart and vessels can be interrogated using Doppler. Measures of cerebral and placental vascular resistance, as well as indirect measures of intracardiac pressure obtained from the velocity waveform in the ductus venosus are routinely used to guide the management of fetal cardiovascular and placental disease. However, the characterization of some key elements of cardiovascular physiology such as vessel blood flow and the oxygen content of blood in the arteries and veins, as well as fetal oxygen delivery and consumption are not readily measured using ultrasound. To study these parameters, we have historically relied on data obtained using invasive measurements made in animal models, which are not equivalent to the human in every respect. Over recent years, a number of technical advances have been made that have allowed us to examine the human fetal circulatory system using cardiovascular magnetic resonance (CMR). The combination of vessel blood flow measurements made using cine phase contrast magnetic resonance imaging and vessel blood oxygen saturation and hematocrit measurements made using T1 and T2 mapping have enabled us to emulate those classic fetal sheep experiments defining the distribution of blood flow and oxygen transport across the fetal circulation in the human fetus. In addition, we have applied these techniques to study the relationship between abnormal fetal cardiovascular physiology and fetal development in the setting of congenital heart disease and placental insufficiency. CMR has become an important diagnostic tool in the assessment of cardiovascular physiology in the setting of postnatal cardiovascular disease, and is now being applied to the fetus to enhance our understanding of normal and abnormal fetal circulatory physiology and its impact on fetal well-being.
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http://dx.doi.org/10.1159/000505091DOI Listing
March 2021

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.

Genet Med 2020 06 10;22(6):1015-1024. Epub 2020 Feb 10.

Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.

Purpose: This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.

Methods: We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.

Results: In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.

Conclusion: This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.
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http://dx.doi.org/10.1038/s41436-020-0757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272322PMC
June 2020

Differential gene responses 3 days following infarction in the fetal and adolescent sheep heart.

Physiol Genomics 2020 03 21;52(3):143-159. Epub 2020 Jan 21.

Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.

There are critical molecular mechanisms that can be activated to induce myocardial repair, and in humans this is most efficient during fetal development. The timing of heart development in relation to birth and the size/electrophysiology of the heart are similar in humans and sheep, providing a model to investigate the repair capacity of the mammalian heart and how this can be applied to adult heart repair. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in fetal (105 days gestation when cardiomyocytes are proliferative) and adolescent sheep (6 mo of age when all cardiomyocytes have switched to an adult phenotype). An ovine gene microarray was used to compare gene expression in sham and infarcted (remote, border and infarct areas) cardiac tissue from fetal and adolescent hearts. The gene response to myocardial infarction was less pronounced in fetal compared with adolescent sheep hearts and there were unique gene responses at each age. There were also region-specific changes in gene expression between each age, in the infarct tissue, tissue bordering the infarct, and tissue remote from the infarction. In total, there were 880 genes that responded to MI uniquely in the adolescent samples compared with 170 genes in the fetal response, as well as 742 overlap genes that showed concordant direction of change responses to infarction at both ages. In response to myocardial infarction, there were specific changes in genes within pathways of mitochondrial oxidation, muscle contraction, and hematopoietic cell lineages, suggesting that the control of energy utilization and immune function are critical for effective heart repair. The more restricted gene response in the fetus may be an important factor in its enhanced capacity for cardiac repair.
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http://dx.doi.org/10.1152/physiolgenomics.00092.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099410PMC
March 2020

Current and future role of fetal cardiovascular MRI in the setting of fetal cardiac interventions.

Prenat Diagn 2020 01 19;40(1):71-83. Epub 2019 Dec 19.

Division of Pediatric Cardiology, Department of Pediatrics, University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.

Over recent years, technical developments resulting in the feasibility of fetal cardiovascular magnetic resonance (CMR) have provided a new diagnostic tool for studying the human fetal heart and circulation. During the same period, we have witnessed the arrival of several minimally invasive fetal cardiac interventions (FCI) as a possible form of treatment in selected congenital heart diseases (CHDs). The role of fetal CMR in the planning and monitoring of FCI is not yet clear. Indeed, high-quality fetal CMR is not available or routinely offered at most centers caring for patients with prenatally detected CHD. However, in theory, fetal CMR could have much to offer in the setting of FCI by providing complementary anatomic and physiologic information relating to the specific intervention under consideration. Similarly, fetal CMR may be useful as an alternative imaging modality when ultrasound is hampered by technical limitations, for example, in the setting of oligohydramnios and in late gestation. In this review, we summarize current experience of the use of fetal CMR in the diagnosis and monitoring of fetuses with cardiopathies in the setting of a range of invasive in utero cardiac and vascular interventions and medical treatments and speculate about future directions for this versatile imaging medium.
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http://dx.doi.org/10.1002/pd.5626DOI Listing
January 2020

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues.

J Biophotonics 2020 03 23;13(3):e201960085. Epub 2019 Dec 23.

Early Origins of Adult Health Research Group, University of South Australia, Adelaide, South Australia, Australia.

The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two-photon microscopy. Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production; whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism.
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http://dx.doi.org/10.1002/jbio.201960085DOI Listing
March 2020