iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Xu, Xiangyan; Jin, Ketao; As, Bais; Zhu, Weiliang; Yagi, Hisato; Tn, Feinstein; Nguyen, Phong K.; Criscione, Joseph D.; Liu, Xiaoyu; Beutner, Gisela; Kb, Karunakaran; Adams, Phillip S.; Ck, Kuo; Kostka, Dennis; Gs, Pryhuber; Shiva, Sruti; Mk, Ganapathiraju; Ga, Porter; Ji, Lin; Aronow, Bruce J.; Cw, Lo

doi:10.1101/2021.05.09.443165

Cited by 4 publications

(3 citation statements)

References 76 publications

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“…In one HLHS patient, a significant increase in mitochondrial respiration was observed before and after heart transplantation, indicating that the metabolic defects in this patient is likely intrinsic and could cause oxidative stress leading to apoptosis and HF. Supporting this possibility, induced pluripotent stem cell-derived cardiomyocytes from HLHS patients with early HF were found to have a failed antioxidant response that could exacerbate metabolic defects causing redox stress (14,15).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease

Lin

Bais

et al. 2021

Front. Cardiovasc. Med.

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Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39–50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD.Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue.Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR.Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease

Lin

Bais

et al. 2021

Front. Cardiovasc. Med.

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“…Transcriptional and structural alterations found in the LV of the HLHS Ohia mice are present, though less severe, in the right ventricle (RV). 10 , 11 This suggests that intrinsic defects in myogenic programs of both ventricles may manifest differently, depending on combinations of the cardiac progenitor (CP) population affected and physiologic milieu.…”

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confidence: 99%

Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome

et al. 2021

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Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent–offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. Conclusions: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

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“…iPSC lines were generated from fibroblasts cells. 51 , 52 All the iPSC cell lines have been cultured in mTeSR medium. Informed consent was obtained from both control and patient with human study protocol approved by the IRB of the University of Pittsburgh.…”

Section: Methodsmentioning

confidence: 99%

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Cited by 4 publications

References 76 publications

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease

Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability

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