Distention of the Immature Left Ventricle Triggers Development of Endocardial Fibroelastosis: An Animal Model of Endocardial Fibroelastosis Introducing Morphopathological Features of Evolving Fetal Hypoplastic Left Heart Syndrome

Shimada, Shogo; Robles, Christian; Illigens, Ben; Berazaluce, Alejandra M. Casar; Nido, Pedro J. del; Friehs, Ingeborg

doi:10.1155/2015/462469

Cited by 15 publications

(16 citation statements)

References 30 publications

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“…Responses to pathologic stimuli such as allotransplantation [16,17] and ischemia-reperfusion injury [18] are also assumed to be different from those of mature adult hearts. By using the present models with modifications, we have shown that an immature heart responds differently upon being exposed to severe distention and develops endocardial fibroelastosis, a unique form of cardiac fibrosis developing on the endocardial surface predominantly in immature hearts [12]. In addition, in the current study we observed that the transplanted neonatal heart developed a rather thickened LV wall after 2 weeks of mechanical unloading.…”

Section: Discussionsupporting

confidence: 50%

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Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model

Shimada

Nido²,

Friehs³

2016

Eur Surg Res

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Background/Purpose: Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. Methods: Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. Results: Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic visualization. Conclusions: We describe detailed surgical techniques for AHTx and FHTx while addressing neonatal donor-specific issues. Following our recommendations potentially reduces the learning curve to achieve reliable and reproducible results with these challenging animal models.

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Section: Discussionsupporting

confidence: 50%

“…We have been studying effects of mechanical load on the immature heart through a heterotopic neonatal rat heart transplantation model [11,12,13]. A specific procedural strategy with several technical refinements was required to overcome innate vulnerability of using neonatal animals as donors.…”

Section: Introductionmentioning

confidence: 99%

Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model

Shimada

Nido²,

Friehs³

2016

Eur Surg Res

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“…Although sub-myocardial ischaemia has been proposed as a cause of EFE, analysis of coronary vasculature in HLHS has not supported this proposal [ 32 , 33 ]. Recent studies have suggested that EFE results from excessive or ectopic endocardial to mesenchymal transformation [ 34 , 35 ]. It is unclear whether this is therefore a specific element in the pathogenesis of this phenotype, in contrast to the miniaturised or slit-like ventricles, or represents a situation where there is reduced but present flow, signalling EFE formation as a secondary response.…”

Section: Discussionmentioning

confidence: 99%

Re-evaluation of hypoplastic left heart syndrome from a developmental and morphological perspective

Crucean

Alqahtani

Barron

et al. 2017

Orphanet J Rare Dis

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BackgroundHypoplastic left heart syndrome (HLHS) covers a spectrum of rare congenital anomalies characterised by a non-apex forming left ventricle and stenosis/atresia of the mitral and aortic valves. Despite many studies, the causes of HLHS remain unclear and there are conflicting views regarding the role of flow, valvar or myocardial abnormalities in its pathogenesis, all of which were proposed prior to the description of the second heart field. Our aim was to re-evaluate the patterns of malformation in HLHS in relation to recognised cardiac progenitor populations, with a view to providing aetiologically useful sub-groupings for genomic studies.ResultsWe examined 78 hearts previously classified as HLHS, with subtypes based on valve patency, and re-categorised them based on their objective ventricular phenotype. Three distinct subgroups could be identified: slit-like left ventricle (24%); miniaturised left ventricle (6%); and thickened left ventricle with endocardial fibroelastosis (EFE; 70%). Slit-like ventricles were always found in combination with aortic atresia and mitral atresia. Miniaturised left ventricles all had normally formed, though smaller aortic and mitral valves. The remaining group were found to have a range of aortic valve malformations associated with thickened left ventricular walls despite being described as either atresia or stenosis. The degree of myocardial thickening was not correlated to the degree of valvar stenosis. Lineage tracing in mice to investigate the progenitor populations that form the parts of the heart disrupted by HLHS showed that whereas Nkx2–5-Cre labelled myocardial and endothelial cells within the left and right ventricles, Mef2c-AHF-Cre, which labels second heart field-derived cells only, was largely restricted to the endocardium and myocardium of the right ventricle. However, like Nkx2–5-Cre, Mef2c-AHF-Cre lineage cells made a significant contribution to the aortic and mitral valves. In contrast, Wnt1-Cre made a major contribution only to the aortic valve. This suggests that discrete cardiac progenitors might be responsible for the patterns of defects observed in the distinct ventricular sub-groups.ConclusionsOnly the slit-like ventricle grouping was found to map to the current nomenclature: the combination of mitral atresia with aortic atresia. It appears that slit-like and miniature ventricles also form discrete sub-groups. Thus, reclassification of HLHS into subgroups based on ventricular phenotype, might be useful in genetic and developmental studies in investigating the aetiology of this severe malformation syndrome.

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“…Studies in rats have provided further support linking impaired hemodynamics and impaired ventricular function to endocardial defects. Thus, distention of the left ventricle caused by surgically induced aortic regurgitation was shown to lead to endocardial injury and endocardial fibroelastosis [30]. We have already cited the studies in the developing chick that show decreased flow across the mitral valve subsequent to ligation of the left atrium can produce a variant of left ventricular hypoplasia [8].…”

Section: The Endocardium In the Setting Of Hypoplastic Left Heart mentioning

confidence: 99%

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

Grossfeld

Nie

Lin

et al. 2019

JCDD

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Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. There is controversy surrounding the mechanisms underlying the syndrome, which is likely due, in part, to the phenotypic variability of the disease. The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. Research has also been hindered by what has been, up until now, a lack of genetically engineered animal models that faithfully reproduce the human disease. There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. In this review, we discuss the evidence demonstrating that, at least for a subset of cases, the chamber hypoplasia is the consequence of hyperplasia of the contained cardiomyocytes. In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome.

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Distention of the Immature Left Ventricle Triggers Development of Endocardial Fibroelastosis: An Animal Model of Endocardial Fibroelastosis Introducing Morphopathological Features of Evolving Fetal Hypoplastic Left Heart Syndrome

Cited by 15 publications

References 30 publications

Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model

Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model

Re-evaluation of hypoplastic left heart syndrome from a developmental and morphological perspective

Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?

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