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A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow.

ABSTRACT: In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term and/or have very low disease penetrance. Here, we report the development of a surgically induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left atrium of embryonic day (E)14.5 mice with an embolizing agent under high-frequency ultrasound guidance, which partially blocks blood flow into the left heart and induces hypoplasia. At term (E18.5), all positively embolized mice exhibit retrograde aortic arch flow, non-apex-forming left ventricles and hypoplastic ascending aortas. We thus report the development of the first mouse model of isolated HLHS with a fully penetrant cardiac phenotype and survival to term. Our method allows for the interrogation of previously intractable questions, such as determining the mechanisms of cardiac hypoplasia and fetal abnormalities observed in HLHS, as well as testing of mechanism-based therapies, which are urgently lacking.

SUBMITTER: Rahman A

PROVIDER: S-EPMC8592017 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow.

Rahman Anum A DeYoung Taylor T Cahill Lindsay S LS Yee Yohan Y Debebe Sarah K SK Botelho Owen O Seed Mike M Chaturvedi Rajiv R RR Sled John G JG

Disease models & mechanisms 20211110 11

In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term and/or have very low disease penetrance. Here, we report the development of a surgically induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left ...[more]

PMID: 34514502

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Project description:Fetuses with critical aortic stenosis (FAS) are at high risk of progression to HLHS by the time of birth (and are thus termed "evolving HLHS"). An in-utero catheter-based intervention, fetal aortic valvuloplasty (FAV), has shown promise as an intervention strategy to circumvent the progression, but its impact on the heart's biomechanics is not well understood. We performed patient-specific computational fluid dynamic (CFD) simulations based on 4D fetal echocardiography to assess the changes in the fluid mechanical environment in the FAS left ventricle (LV) directly before and 2 days after FAV. Echocardiograms of five FAS cases with technically successful FAV were retrospectively analysed. FAS compromised LV stroke volume and ejection fraction, but FAV rescued it significantly. Calculations to match simulations to clinical measurements showed that FAV approximately doubled aortic valve orifice area, but it remained much smaller than in healthy hearts. Diseased LVs had mildly stenotic mitral valves, which generated fast and narrow diastolic mitral inflow jet and vortex rings that remained unresolved directly after FAV. FAV further caused aortic valve damage and high-velocity regurgitation. The high-velocity aortic regurgitation jet and vortex ring caused a chaotic flow field upon impinging the apex, which drastically exacerbated the already high energy losses and poor flow energy efficiency of FAS LVs. Two days after the procedure, FAV did not alter wall shear stress (WSS) spatial patterns of diseased LV but elevated WSS magnitudes, and the poor blood turnover in pre-FAV LVs did not significantly improve directly after FAV. FAV improved FAS LV's flow function, but it also led to highly chaotic flow patterns and excessively high energy losses due to the introduction of aortic regurgitation directly after the intervention. Further studies analysing the effects several weeks after FAV are needed to understand the effects of such biomechanics on morphological development.

Project description:BackgroundAortic coarctation (CoA) is a congenital heart disease that usually combines various cardiovascular malformations, including hypoplastic aortic arch (HAA). We explore end-to-side anastomosis (ESA) and autologous pulmonary artery patch (APAP) in CoA with HAA, to provide more clinical experience.MethodsThis is a single-center retrospective study. The target population is patients with aortic stenosis and HAA who underwent surgery between 2015 and 2021. All cases included were consecutive, and no instances were omitted due to absent data, lack of consent, or other factors. Collect information on gender, age, and weight at the time of the operation, detailed information on the constricted segment and pressure gradient evaluated by echocardiography and computed tomography (CT), and other factors of patients, and these data were analyzed by statistical methods.ResultsNinety-six patients (67 males and 29 females) with median age of 76 (41.75, 128.50) days and median weight of 4.20 (3.70, 5.10) kg were enrolled. The follow-up period was 46.20 (34.40, 54.70) months. The patients were divided into two groups based on surgery: ESA (G1, 59) and APAP (G2, 37). The combined cardiovascular malformations were treated simultaneously. None of the patients had neurological events or renal failure, and three died early after the operation. Finally, 93 patients were successfully followed-up. Cox regression showed that ESA was a risk factor for aortic arch geometry is closer to Gothic (G-AAg), elevated blood pressure (EBp), and aortic recoarctation (reCoA) after surgery. In G1, 18 patients had G-AAg (P=0.03), 13 had EBp (P=0.041), and 12 had reCoA (P=0.041), all of which were significantly higher than those in G2 (three had G-AAg, one of whom had EBp and reCoA).ConclusionsIt is safe and effective to repair CoA and HAA and other cardiovascular malformations through one-stage median sternotomy. Compared with ESA, APAP can lower the risks of G-AAg, EBp, and reCoA. Although APAP takes longer, the proper application of selective antegrade cerebral perfusion may lower the risks. We recommend expanding the indications for APAP when circumstances allow, which will benefit patients.

Dataset Information

A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow.

Publications

A mouse model of hypoplastic left heart syndrome demonstrating left heart hypoplasia and retrograde aortic arch flow.

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