Abstract P114: Evidence of Transplacental Antibody Transfer in Proposed Animal Model for Hypoplastic Left Heart Syndrome

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Charles R Cole ◽  
Mitali Basu ◽  
R Scott Baker ◽  
Chris Lam ◽  
Adita Blanco ◽  
...  
Keyword(s):  
Animal Model ◽  
Heart Disease ◽  
Hypoplastic Left Heart Syndrome ◽  
Elevated Serum ◽  
Left Heart ◽  
Variable Response ◽  
Hypoplastic Left Heart ◽  
Antibody Titers ◽  
Near Term ◽  
Left Heart Syndrome

Background: The pathogenesis of Hypoplastic Left Heart Syndrome (HLHS), a congenital heart disease with significant morbidity and mortality, remains unknown. We previously proposed a hypothesis wherein HLHS represents a type of rheumatic heart disease in the fetus; trans-placental passage of maternal anti-strep or anti-cardiac myosin (CM) antibodies are postulated to play a key role in the pathogenesis of disease. This is a first report of an animal model that we have developed to assess our hypothesis. Methods: Female Lewis rats (∼ 8 weeks old) were immunized with either streptococcal antigen M type 5 S. pyogenes (PepM5; n=6), rat CM (n=8) or saline (controls; n=5) with three booster injections administered at 2-week intervals. Serum titers of acquired PepM5 or CM antibodies were determined by ELISA assays every 7–14 days. No boosters were administered during gestation. Trans-uterine echocardiography was performed near term (E19-21) to determine fetal number and viability then cesarean section was performed under anesthesia to deliver the progeny. Maternal and fetal serum and hearts were harvested for analysis. Results: All rats immunized with PepM5 had elevated serum anti-PepM5 antibody titers (>1:12800) and two of these animals also had elevated anti-CM titers (1:800). The offspring of these PepM5 immunized animals had elevated anti-PepM5 antibody titers (≥1:6400), but no CM elevation. Rats immunized with CM had a variable response ranging from anti-CM titers of 1:1600 to >1:12800; there were two non-responders. Their fetuses had anti-CM titers that ranged from 1:100 to 1:800. None of the controls had detectable serum titers. Fetal CM titers of ≥1:200 correlate with maternal peak CM titers of ≥1:6400 and/or maternal harvest titers of ≥1:800. Thus far, 6 of the CM treated fetuses have evidence of left-sided morphologic abnormalities along a variable spectrum; all of these fetuses had CM titers of ≥1:200. Conclusion: We have documented maternal antibody response and trans-placental antibody transfer from maternal rats immunized with CM or PepM5 prior to pregnancy. Anti-CM antibody does not cross the placental as readily as PepM5. Preliminary histologic findings demonstrate probable HLHS phenotype, which appears to correlate with fetal antibody titer.

scholarly journals 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

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shogo Shimada ◽  
Christian Robles ◽  
Ben M. W. Illigens ◽  
Alejandra M. Casar Berazaluce ◽  
Pedro J. del Nido ◽  
...  
Keyword(s):  
Animal Model ◽  
Left Ventricle ◽  
Hypoplastic Left Heart Syndrome ◽  
Left Heart ◽  
Endocardial Fibroelastosis ◽  
Hypoplastic Left Heart ◽  
Fetal Imaging ◽  
Adult Rat ◽  
Human Fetal Heart ◽  
Left Heart Syndrome

Background.Endocardial fibroelastosis (EFE), characterized by a diffuse endocardial thickening through collagen and elastin fibers, develops in the human fetal heart restricting growth of the left ventricle (LV). Recent advances in fetal imaging indicate that EFE development is directly associated with a distended, poorly contractile LV in evolving hypoplastic left heart syndrome (HLHS). In this study, we developed an animal model of EFE by introducing this human fetal LV morphopathology to an immature rat heart.Methods and Results.A neonatal donor heart, in which aortic regurgitation (AR) was created, was heterotopically transplanted into a recipient adult rat. AR successfully induced the LV morphology of evolving HLHS in the transplanted donor hearts, which resulted in the development of significant EFE covering the entire LV cavity within two weeks postoperatively. In contrast, posttransplants with a competent aortic valve displayed unloaded LVs with a trace of EFE.Conclusions.We could show that distention of the immature LV in combination with stagnant flow triggers EFE development in this animal model. This model would serve as a robust tool to develop therapeutic strategies to treat EFE while providing insight into its pathogenesis.

Inotropes in the hypoplastic left heart syndrome: Effects in an animal model

1996 ◽  
Vol 62 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Christopher J. Riordan ◽  
Flemming Randsbaek ◽  
John H. Storey ◽  
William D. Montgomery ◽  
William P. Santamore ◽  
...  
Keyword(s):  
Animal Model ◽  
Hypoplastic Left Heart Syndrome ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Left Heart Syndrome

scholarly journals Genetic Association between Hypoplastic Left Heart Syndrome and Cardiomyopathies

2020 ◽  
Author(s):  
Jeanne L. Theis ◽  
Jessie J. Hu ◽  
Rhianna S. Sundsbak ◽  
Jared M. Evans ◽  
William R. Bamlet ◽  
...  
Keyword(s):  
Heart Disease ◽  
Whole Genome Sequencing ◽  
Hypoplastic Left Heart Syndrome ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Degree Relative ◽  
Fourth Degree ◽  
Left Heart Syndrome

Background - Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease. Methods - Whole genome sequencing (WGS) was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in three index families comprised of an HLHS proband and relative(s) with cardiomyopathy. WGS data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction. Results - A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular non-compaction (LVNC), and two fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) and his father with LVNC and CPVT. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 ( P =0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort-four with familial congenital heart disease, four with compound heterozygosity (three with systolic ventricular dysfunction), and four with MYH6-FLNC synergistic heterozygosity. Conclusions - Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

scholarly journals Patient-specific functional genomics and disease modeling suggest a role for LRP2 in hypoplastic left heart syndrome

2019 ◽  
Author(s):  
Jeanne L. Theis ◽  
Georg Vogler ◽  
Maria A. Missinato ◽  
Xing Li ◽  
Almudena Martinez-Fernandez ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Hypoplastic Left Heart Syndrome ◽  
Congenital Heart ◽  
Whole Genome ◽  
Left Heart ◽  
Heart Model ◽  
Hypoplastic Left Heart ◽  
Left Heart Syndrome ◽  
Human Ipsc

ABSTRACTCongenital heart diseases (CHD), such as hypoplastic left heart syndrome (HLHS), are considered to have complex genetic underpinnings that are poorly understood. Here, an integrated multi-disciplinary approach was applied to identify novel genes and underlying mechanisms associated with HLHS. A family-based strategy was employed that coupled whole genome sequencing (WGS) with RNA sequencing of patient-derived induced pluripotent stem cells (iPSCs) from a sporadic HLHS proband-parent trio to identify, prioritize and functionally evaluate candidate genes in model systems. Consistent with the hypoplastic phenotype, the proband’s iPSCs had reduced proliferation capacity. Filtering WGS for rare de novo, recessive, and loss-of-function variants revealed 10 candidate genes with recessive variants and altered expression compared to the parents’ iPSCs. siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiac progenitors and in the in vivo Drosophila heart model revealed that LDL receptor related protein LRP2 and apolipoprotein APOB are required for robust hiPSC-derived cardiomyocyte proliferation and normal hear structure and function, possibly involving an oligogenic mechanism via growth-promoting WNT and SHH signaling. LRP2 was further validated as a CHD gene in a zebrafish heart model and rare variant burden testing in an HLHS cohort. Collectively, this cross-functional genetic approach to complex congenital heart disease revealed LRP2 dysfunction as a likely novel genetic driver of HLHS, and hereby established a scalable approach to decipher the oligogenic underpinnings of maladaptive left heart development.One sentence summaryWhole genome sequencing and a multi-model system candidate gene validation - human iPSC-derived cardiomyocytes and Drosophila and zebrafish hearts - identified lipoprotein LRP2 as a new potential driver in congenital heart disease and suggests a deficit in proliferation as a hallmark of hypoplastic left heart syndrome.

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