MRI Characterization of Blood Flow and Oxygen Delivery in the Fetal Sheep whilst Exposed to Sildenafil Citrate

Abstract

<b><i>Introduction:</i></b> Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. <b><i>Methods:</i></b> At 116–117 days gestational age (term, 150 days), pregnant Merino ewes (<i>n</i> = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T<sub>2</sub> oximetry. <b><i>Results:</i></b> Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. <b><i>Conclusion:</i></b> SC induces alterations to pulmonary haemodynamics <i>in utero</i>; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.

Phenotype of early-onset fetal growth restriction in sheep

“…Unfortunately, the STRIDER trial was halted prematurely due to an indication in the Dutch STRIDER study that sildenafil may have been associated with an increased rate of neonatal death ( 53 ). This finding supports the strong need to firstly assess the effects of treatments in well characterised animal models of FGR ( 23 , 54 , 55 ).…”

Advanced imaging of fetal cardiac function

“…Thus, the cardiovascular magnetic resonance techniques that are routinely used for the non-invasive assessment of ventricular function in postnatal patients have been applied in fetal sheep to quantify myocardial mass and right and left ventricular volumes and ejection fractions. Fetal CMR with late gadolinium enhancement has also been used to detect cardiac damage in an experimental model of infarction ( 44 , 153 ) and to measure vessel flow and oxygen content ( 48 , 154 ) in an attempt to emulate the invasive hemodynamic measurements made in fetal sheep that have defined our modern understanding of normal fetal circulatory physiology. Similarly, through the development of alternatives to conventional ECG gating, accelerated imaging and motion correction algorithms, this combination of vessel flow and oximetry measurements has been applied in human fetuses to explore the normal circulation ( 154 ) as well as the impact of congenital heart malformations and vasoactive agents ( 48 ) on fetal circulatory physiology ( 37 , 43 ).…”

“…Fetal CMR with late gadolinium enhancement has also been used to detect cardiac damage in an experimental model of infarction ( 44 , 153 ) and to measure vessel flow and oxygen content ( 48 , 154 ) in an attempt to emulate the invasive hemodynamic measurements made in fetal sheep that have defined our modern understanding of normal fetal circulatory physiology. Similarly, through the development of alternatives to conventional ECG gating, accelerated imaging and motion correction algorithms, this combination of vessel flow and oximetry measurements has been applied in human fetuses to explore the normal circulation ( 154 ) as well as the impact of congenital heart malformations and vasoactive agents ( 48 ) on fetal circulatory physiology ( 37 , 43 ). The potential role of fetal CMR as an adjunct to ultrasound has also been investigated in the setting of severe fetal hemodynamic compromise, for example in patients undergoing fetal cardiac interventions ( 37 , 56 ).…”

“…While administering gadolinium contrast agents is contraindicated in pregnant patients, a combination of late gadolinium enhancement and cardiac cine imaging has been used to evaluate the biology of myocardial infarctions and ventricular function in preclinical fetal and postnatal sheep studies (44,45). A combination of vessel flow and magnetic resonance oximetry has also been applied in sheep to assess the distribution of blood flow and oxygen transport across the fetal circulation, and as an approach to comprehensively quantifying the placental oxygen transfer (31,(46)(47)(48)(49)(50)(51). Fetal CMR has been used in human pregnancies to study the effect of congenital cardiac malformations on fetal cardiovascular physiology, particularly through the implementation of cine phase contrast for quantifying vessel flow and relaxometry for characterizing vessel oxygen saturation and hematocrit, techniques that have also been applied in the setting of fetal growth restriction and anemia (19,25,29,33,37,38,50,(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64).…”

Acute resveratrol exposure does not impact hemodynamics of the fetal sheep

“…We have previously validated the use of phase‐contrast (PC)‐magnetic resonance imaging (MRI) and T 2 oximetry to measure blood flow and oxygen saturation to then calculate oxygen delivery within the circulations of both the human and sheep fetus (Saini et al, 2020 ). Moreover, the combination of these two clinically relevant MRI techniques has proven useful in understanding the impact that vasoactive compounds have on fetal hemodynamics (Darby, Schrauben, et al, 2020 ; Dimasi et al, 2021 ; Duan et al, 2019 ; Morrison et al, 2022 ; Saini et al, 2020 ). Herein, we aimed to utilize these advanced MRI techniques to determine the direct impact that RSV has on the hemodynamics of the fetal sheep.…”