Fibrosis-Related Gene Expression in Single Ventricle Heart Disease

Abstract

Objective To evaluate fibrosis and fibrosis-related gene expression in the myocardium of pediatric single ventricle (SV) subjects with right ventricular (RV) failure. Study design Real-time quantitative polymerase chain reaction was performed on explanted RV myocardium of pediatric SV subjects and non-failing controls. Subjects were divided into 3 groups: SV failing (SV-F, RV failure prior to or following Stage I palliation), SV non-failing (SV-NF, infants listed for primary transplant with normal RV function), and Stage III (Fontan or RV failure following Stage III). In order to evaluate subjects of similar age and RV volume loading, SV-F was compared with SV-NF and Stage III was compared with NF RV. Histologic fibrosis was assessed in all hearts. Mann-Whitney tests were performed to identify differences in gene expression. Results Collagen (Col1α, Col3) expression is decreased in SV-F compared with SV-NF (P = .019 and p=0.035, respectively), and is equivalent in Stage III compared with NF RV. Tissue inhibitors of metalloproteinase (TIMPs1, 3 and 4) are down-regulated in Stage III compared with NF RV (p=0.0047, p=0.013 and p=0.013, respectively). Matrix metalloproteinases (MMP2, MMP9) are similar between SV-NF and SV-F, and between Stage III and NF RV. There is no difference in the prevalence of RV fibrosis by histology in SV subjects with RV failure (18%) compared with those with normal RV function (38%). Conclusions Fibrosis is not a primary contributor to RV failure in infants and young children with SV. Additional studies are required to understand whether anti-fibrotic therapies are beneficial in this population.

Cardiovascular Drug Therapy during Interstage After Hybrid Approach: A Single-Center Experience in 51 Newborns with Hypoplastic Left Heart

“…Parents are carefully taught to monitor the surrogate parameters or HR and especially respiratory rate at rest; extensive monitoring of pulse oximetry at home is neither necessary nor comparably meaningful. We used the mineralocorticoid blocker spironolactone in relatively low, mainly non-diuretic dosages in approximately 80% of our patients, even though cardiac fibrosis is less pronounced in infants and small children [ 28 ]. Furthermore, we preferentially used the long-acting tissue ACEI lisinopril for additional balancing of pulmonary and systemic circulation, particularly in terms of persistence of high systemic vascular resistance following stage I.…”

Single-Cell RNA Sequencing and Quantitative Proteomics Analysis Elucidate Marker Genes and Molecular Mechanisms in Hypoplastic Left Heart Patients With Heart Failure

“…Cardiac fibrosis has been detected in HLH by histopathology ( Kido et al, 2018 ). Increased angiotensin II and aldosterone levels promote collagen synthesis and reduce collagen breakdown by regulating matrix metalloproteinases, thereby inducing extracellular matrix (ECM) homeostasis ( Nakano et al, 2017 ). Radosinska et al (2017) found that ECM homeostasis was considered a structural and physiological foundation of the heart and that matrix metalloproteinases (MMPs) are an important environmental mediator of cardiac diastolic or systolic dysfunction ( Radosinska et al, 2017 ).…”

Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart

“…A loss of collagen fibrils is associated with LV remodelling during volume overload and with ECM remodelling in dilated cardiomyopathy [ 61 ]. Decreased collagen expression has been reported in children with failing single ventricle congenital heart disease [ 62 ]. Although, based on our current data, we cannot determine whether reduced collagen content represents adverse ECM remodelling that predisposes to cardiac dysfunction, our results clearly indicate that the exposure to maternal diabetes and Hif1a haploinsufficiency significantly affect ECM structure and composition compared with a normal myocardium.…”