Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

Tatman, Philip D.; Woulfe, Kathleen C.; Karimpour-Fard, Anis; Jeffrey, Danielle A.; Jaggers, James; Cleveland, Joseph C.; Nunley, Karin; Taylor, Matthew R.G.; Miyamoto, Shelley D.; Stauffer, Brian L.; Sucharov, Carmen C.

doi:10.1172/jci.insight.94249

Cited by 39 publications

(50 citation statements)

References 37 publications

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“…Notably, in some cases an increase in MDK gene expression does not always lead to translation into protein [ 26 , 27 ], although this has not been thoroughly investigated in all MDK-expressing organs/conditions. We recently showed that in pediatric patients with HF, there is elevated myocardial MDK mRNA expression [ 57 ] and increased protein levels (unpublished data). In addition, MDK expression in pediatric patients is age-dependent ( Figure 2 ) but it is unclear if increased myocardial MDK affects other intracellular targets or is secreted, thereby affecting extracellular receptors in a paracrine or autocrine manner.…”

Section: Intracellular Mdkmentioning

confidence: 99%

Midkine’s Role in Cardiac Pathology

Woulfe

Sucharov

2017

JCDD

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Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF.

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Section: Intracellular Mdkmentioning

confidence: 99%

Midkine’s Role in Cardiac Pathology

Woulfe

Sucharov

2017

JCDD

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“…␤-AR stimulation increases phosphorylation of the RyR2 channel, but there is a lack of consensus about how phosphorylation at three well-documented sites (Ser 2030 , Ser 2808 , and Ser 2814 ) affects the function of the RyR2 channel (22,23,43,(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). It has been suggested that phosphorylation of RyR2 at Ser 2808 and Ser 2814 occurs during HF, and this phosphorylation increases Ca 2ϩ leak from the sarcoplasmic reticulum (4, 24, 26, 42a, 51, 56, 69).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, therapies that improve outcomes in adult patients with IDC fail to provide such benefits in pediatric patients with IDC (54,55,65). We have previously shown fundamental differences in the myocellular mechanisms involved in cardiac pathology between children and adults with IDC, which we propose lead to differences in response to therapies (7,38,42,63,71). Further investigation of these differences will improve understanding of both patient populations and ultimately lead to identification of age-specific targeted treatments that could improve clinical outcomes.…”

Section: Introductionmentioning

confidence: 94%

Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

Woulfe

Wilson

Nau

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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Sudden cardiac death from ventricular arrhythmias is more common in adult patients with with heart failure compared with pediatric patients with heart failure. We identified age-specific differences in arrhythmogenesis using a guinea pig model of acute β-adrenergic stimulation. Young and adult guinea pigs were exposed to the β-adrenergic agonist isoproterenol (ISO; 0.7 mg/kg) for 30 min in the absence or presence of flecainide (20 mg/kg), an antiarrhythmic that blocks Na and ryanodine channels. Implanted cardiac monitors (Reveal LINQ, Medtronic) were used to monitor heart rhythm. Alterations in phosphorylation and oxidation of ryanodine receptor 2 (RyR2) were measured in left ventricular tissue. There were age-specific differences in arrhythmogenesis and sudden death associated with acute β-adrenergic stimulation in guinea pigs. Young and adult guinea pigs developed arrhythmias in response to ISO; however, adult animals developed significantly more premature ventricular contractions and experienced higher arrhythmia-related mortality than young guinea pigs treated with ISO. Although there were no significant differences in the phosphorylation of left ventricular RyR2 between young and adult guinea pigs, adult guinea pigs exposed to acute ISO had significantly more oxidation of RyR2. Flecainide treatment significantly improved survival and decreased the number of premature ventricular contractions in young and adult animals in association with lower RyR2 oxidation. Adult guinea pigs had a greater propensity to develop arrhythmias and suffer sudden death than young guinea pigs when acutely exposed to ISO. This was associated with higher oxidation of RyR2. The incidence of sudden death can be rescued with flecainide treatment, which decreases RyR2 oxidation. NEW & NOTEWORTHY Clinically, adult patients with heart failure are more likely to develop arrhythmias and sudden death than pediatric patients with heart failure. In the present study, older guinea pigs also showed a greater propensity to arrhythmias and sudden death than young guinea pigs when acutely exposed to isoproterenol. Although there are well-described age-related cardiac structural changes that predispose patients to arrhythmogenesis, the present data suggest contributions from dynamic changes in cellular signaling also play an important role in arrhythmogenesis.

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“…Taken together, these data provide novel mechanistic evidence of the contribution of the cardiac chronic hypoxic state to ToF pathogenesis. On the basis of published findings suggesting age-associated changes in the expression of genes encoding molecules associated with extracellular matrix, cytoskeletal structure, collagen deposition, adhesion, and transcription in both mice and human hearts [40][41][42][43], it is possible that the observed gene alterations in ToF respect to ASD patients may result from a combined effect of disease state and lower patient age. Further large-scale studies are needed to specifically address this issue.…”

Section: Table 2 Hypoxia-related Gene Sets Enriched In Tof Vs Asd Sammentioning

confidence: 99%

Transcriptome analysis defines myocardium gene signatures in children with ToF and ASD and reveals disease-specific molecular reprogramming in response to surgery with cardiopulmonary bypass

et al. 2020

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Background: Tetralogy of Fallot (ToF) and Atrial Septal Defects (ASD) are the most common types of congenital heart diseases and a major cause of childhood morbidity and mortality. Cardiopulmonary bypass (CPB) is used during corrective cardiac surgery to support circulation and heart stabilization. However, this procedure triggers systemic inflammatory and stress response and consequent increased risk of postoperative complications. The aim of this study was to define the molecular bases of ToF and ASD pathogenesis and response to CPB and identify new potential biomarkers. Methods: Comparative transcriptome analysis of right atrium specimens collected from 10 ToF and 10 ASD patients was conducted before (Pre-CPB) and after (Post-CPB) corrective surgery. Total RNA isolated from each sample was individually hybridized on Affymetrix HG-U133 Plus Array Strips containing 38,500 unique human genes. Differences in the gene expression profiles and functional enrichment/network analyses were assessed using bioinformatic tools. qRT-PCR analysis was used to validate gene modulation. Results: Pre-CPB samples showed significant differential expression of a total of 72 genes, 28 of which were overexpressed in ToF and 44 in ASD. According to Gene Ontology annotation, the mostly enriched biological processes were represented by matrix organization and cell adhesion in ToF and by muscle development and contractility in ASD specimens. GSEA highlighted the specific enrichment of hypoxia gene sets in ToF samples, pointing to a role for hypoxia in disease pathogenesis. The post-CPB myocardium exhibited significant alterations in the expression profile

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Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

Cited by 39 publications

References 37 publications

Midkine’s Role in Cardiac Pathology

Midkine’s Role in Cardiac Pathology

Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

Transcriptome analysis defines myocardium gene signatures in children with ToF and ASD and reveals disease-specific molecular reprogramming in response to surgery with cardiopulmonary bypass

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