Fetal hypoxemia causes abnormal myocardial development in a preterm ex utero fetal ovine model

Lawrence, Kendall M.; Hennessy-Strahs, Samson; McGovern, Patrick E.; Mejaddam, Ali Y.; Rossidis, Avery C.; Baumgarten, Heron D.; Bansal, Esha; Villeda, Maryann; Han, Jiancheng; Gou, Zhongshan; Zhao, Sen; Rychik, Jack; Peranteau, William H.; Davey, Mary‐Ann; Flake, Alan W.; Gaynor, J. William; Bartoli, Carlo

doi:10.1172/jci.insight.124338

Cited by 17 publications

(19 citation statements)

References 38 publications

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“…Myocardial contractility, mostly of the RV, is diminished early on but recovers. Further investigation of the impact of EXTEND on the cardiovascular system and other organs is underway, as we move toward the aspiration of applying this novel technology in the human fetus.…”

Section: Discussionmentioning

confidence: 99%

Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system

Ozawa

Davey

Tian

et al. 2020

Ultrasound in Obstet & Gyne

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Objective EXTrauterine Environment for Neonatal Development (EXTEND) is a system to support ongoing fetal growth and organ development in an extrauterine environment, utilizing a pumpless low‐resistance oxygenator circuit. The aim of this study was to evaluate hemodynamics and cardiac function in fetal sheep sustained on the EXTEND system. Methods This was a prospective study of fetal sheep supported for a minimum of 3 weeks on EXTEND. Hemodynamic parameters were assessed weekly and included heart rate, mean arterial pressure (MAP), Doppler‐echocardiography‐derived cardiac output (CO), pulsatility indices (PIs) of the fetal middle cerebral artery (MCA), umbilical artery (UA) and ductus venosus and cardiac function, as assessed by speckle‐tracking‐derived global longitudinal strain and strain rate in the right (RV) and left (LV) ventricles. Parameters were compared at 0 days and 1, 2 and 3 weeks following placement on EXTEND. Results Of 10 fetal sheep enrolled, seven survived for 3 weeks and were included in the analysis. Median gestational age at cannulation was 107 (range, 95–109) days. Heart rate decreased and MAP increased significantly, but within acceptable ranges, during the study period. The quantities and relative ratios of right and left CO remained stable within the anticipated physiological range throughout the study period. Vascular tracings and PIs appeared to be similar to those seen normally in the natural in‐utero state, with MCA‐PI being higher than UA‐PI. UA tracings demonstrated maintained abundant diastolic flow despite the absence of placental circulation. In both the RV and LV, strain decreased significantly at 1 and 2 weeks relative to baseline but returned to baseline values by week 3. Conclusions The EXTEND mechanical support system replicates natural physiology and creates a stable and sustainable cardiovascular construct that supports growth over a 3‐week period. However, there is a period of depressed contractility within the first week with subsequent improvement by week 3. This may reflect a period of physiological accommodation that warrants further investigation. This study lays the foundation for further exploration as the EXTEND system moves towards human application. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

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Section: Discussionmentioning

confidence: 99%

Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system

Ozawa

Davey

Tian

et al. 2020

Ultrasound in Obstet & Gyne

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“…Ewe anesthesia, fetal cannulation technique, and the Extra-uterine Environment for Neonatal Development (EXTEND) support device have been described previously in detail. [14][15][16] In brief, 8 fetal sheep at gestational age (GA) 109 AE 3 days (term $145 days) were exteriorized via laparotomy and hysterotomy from time-dated ewes. Fetuses were then cannulated via their umbilical vessels and attached to a pumpless low resistance oxygenator circuit.…”

Section: Methods Animal Surgery and Supportmentioning

confidence: 99%

Prenatal hypoxemia alters microglial morphology in fetal sheep

Lawrence

McGovern

Mejaddam

et al. 2020

The Journal of Thoracic and Cardiovascular Surgery

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“…AW models also provide a controlled environment to study the pathophysiology of abnormal conditions, for example, fetal hypoxia. 116,[121][122][123] The current animal models can evaluate potential therapeutic benefit of AW models for indications other than extreme prematurity. For example, fetal growth restriction caused by placental insufficiency may be reversed through delivery onto an AW model, ensuring adequate oxygen delivery and optimal nutrition, and early delivery on AW model may prove to be beneficial in the…”

Section: Aw Technology As Research Modelmentioning

confidence: 99%

“…Reduced cardiac contractility was temporarily noted during a 1‐week accommodation phase on circuit, after which normal cardiac function and contractility were present for the rest of the run 115 . In lambs supported by EXTEND for 19 to 25 days, no myocardial injury or inflammation was found, and cardiac development and structure was normal compared to age‐matched controls 116 . Specific assessment of the liver and kidney has not been reported yet.…”

Section: Current Successful Ap and Aw Models: Design And Outcomesmentioning

confidence: 99%

“…In addition to its promising clinical potential, AW technology provides a novel research model to address fundamental questions regarding fetal physiology, such as the roles and contributions of the placenta and maternal hormones and growth factors to normal fetal development. AW models also provide a controlled environment to study the pathophysiology of abnormal conditions, for example, fetal hypoxia 116,121‐123 . The current animal models can evaluate potential therapeutic benefit of AW models for indications other than extreme prematurity.…”

Section: Aw Technology As Research Modelmentioning

confidence: 99%

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Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

et al. 2020

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Extreme prematurity remains a major cause of neonatal mortality and severe long‐term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb‐like environment, is the foundational principle of artificial placenta (AP) and womb (AW) technology. The concept has been studied during the past 60 years with limited success. However, recent technological advancements and a greater emphasis on mimicking utero‐placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here, we review the rationale for and history of AP and AW technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research.

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Fetal hypoxemia causes abnormal myocardial development in a preterm ex utero fetal ovine model

Cited by 17 publications

References 38 publications

Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system

Fetal echocardiographic assessment of cardiovascular impact of prolonged support on EXTrauterine Environment for Neonatal Development (EXTEND) system

Prenatal hypoxemia alters microglial morphology in fetal sheep

Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

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