Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction.

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V).

JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency.

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions.

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.

Background: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging.

Objectives: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors.

Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure.

Genetic Diagnosis and the Severity of Cardiovascular Phenotype in Patients With Elastin Arteriopathy.

Background: Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene () causes Williams-Beuren syndrome (WBS), while single nucleotide variants in cause nonsyndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and nonsyndromic SVAS.

Association between genetic variants in the HIF1A-VEGF pathway and left ventricular regional myocardial deformation in patients with hypertrophic cardiomyopathy.

Background: Information on genetic etiology of pediatric hypertrophic cardiomyopathy (HCM) rarely aids in risk stratification and prediction of disease onset. Little data exist on the association between genetic modifiers and phenotypic expression of myocardial performance, hampering an individual precision medicine approach.

Methods: Single-nucleotide polymorphism genotyping for six previously established disease risk alleles in the hypoxia-inducible factor-1α-vascular endothelial growth factor pathway was performed in a pediatric cohort with HCM.

Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells.

Objective: Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells-derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients.

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC).

Abnormal fetal cerebral and vascular development in hypoplastic left heart syndrome.

Objective: To assess the cerebral and vascular development in fetuses with hypoplastic left heart syndrome (HLHS).

Methods: Pregnant women carrying fetuses diagnosed with HLHS who decided to interrupt their pregnancies were included in our study. Aortic size and blood flow were assessed based from fetal echocardiography.

Fetal reprogramming and senescence in hypoplastic left heart syndrome and in human pluripotent stem cells during cardiac differentiation.

Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by left ventricle (LV) hypoplasia and abnormal LV perfusion and oxygenation. We studied hypoxia-associated injury in fetal HLHS and human pluripotent stem cells during cardiac differentiation to assess the effect of microenvironmental perturbations on fetal cardiac reprogramming. We studied LV myocardial samples from 32 HLHS and 17 structurally normal midgestation fetuses.

Modeling and rescue of the vascular phenotype of Williams-Beuren syndrome in patient induced pluripotent stem cells.

Elastin haploinsufficiency in Williams-Beuren syndrome (WBS) leads to increased vascular smooth muscle cell (SMC) proliferation and stenoses. Our objective was to generate a human induced pluripotent stem (hiPS) cell model for in vitro assessment of the WBS phenotype and to test the ability of candidate agents to rescue the phenotype. hiPS cells were reprogrammed from skin fibroblasts of a WBS patient with aortic and pulmonary stenosis and healthy control BJ fibroblasts using four-factor retrovirus reprogramming and were differentiated into SMCs.

Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype.

Background: Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigated the association of variants in hypoxia-response genes with phenotype severity in pediatric HCM.

Methods: A total of 80 unrelated patients <21 y and 14 related members from eight families with HCM were genotyped for six variants associated with vascular endothelial growth factor A (VEGFA) downregulation, or hypoxia-inducible factor A (HIF1A) upregulation.

Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair.

Background: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair.

Methods: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A.

Recipient genotype is a predictor of allograft cytokine expression and outcomes after pediatric cardiac transplantation.

Objectives: This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.

Background: The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation.

LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor.

Previously, we related fibronectin (Fn1) mRNA translation to an interaction between an AU-rich element in the Fn1 3' UTR and light chain 3 (LC3) of microtubule-associated proteins 1A and 1B. Since human fibrosarcoma (HT1080) cells produce little fibronectin and LC3, we used these cells to investigate how LC3-mediated Fn1 mRNA translation might alter tumor growth. Transfection of HT1080 cells with LC3 enhanced fibronectin mRNA translation.

Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptor.

Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12-14/group): control (vehicle); nitro-L-arginine methyl ester (L-NAME) an NO synthase inhibitor; simvastatin (SIM), an NO synthase activator; and SIM+L-NAME.

Preservation of mitochondrial structure and function after cardioplegic arrest in the neonate using a selective mitochondrial KATP channel opener.

Background: Mitochondrial dysfunction may contribute to early postoperative neonatal heart dysfunction. Diazoxide, a mitochondrial-selective adenosine triphosphate-sensitive potassium-channel opener, is associated with mitochondrial preservation after cardioplegic arrest. We evaluated the mitochondrial-protective effect of diazoxide in terms of mitochondrial structure and function after neonatal cardioplegic arrest.

Apolipoprotein D inhibits platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferated by preventing translocation of phosphorylated extracellular signal regulated kinase 1/2 to the nucleus.

Objective: Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease.

Methods And Results: Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery.