Gene expression and β-adrenergic signaling are altered in hypoplastic left heart syndrome

Abstract

BACKGROUND The purpose of the current study was to define the myocellular changes and adaptation of the β-adrenergic receptor (β-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS Explanted hearts from children with HLHS and non-failing controls were used for this study. HLHS patients were divided into 2 groups: “compensated” (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and “decompensated” (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and α-myosin heavy chain (MHC) gene expression, decreased total β-AR due to down-regulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased β-MHC and decreased α-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of β1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the β-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.

Micro-RNA Expression in Hypoplastic Left Heart Syndrome

“…A detailed description of all pediatric patients can be found in Table S1. In table S1, RV failure is defined as signs and symptoms of heart failure in the setting of abnormal systolic function on echocardiogram, low cardiac output measured at catheterization [cardiac index below 2.5 L/min/m 2 ] and/or diastolic dysfunction of the RV [end diastolic pressure of the RV >12mmHg] (3). Informed consent was obtained from all patients.…”

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease

“…Prior analyses of cAMP levels in SRV disease have demonstrated similar levels of myocardial cAMP between nonfailing RV and SV 17 . The current study focuses on SRV with heart failure (excluding patients with “compensated” disease) and encompasses a larger number of subjects.…”

Cardiac Adenylyl Cyclase and Phosphodiesterase Expression Profiles Vary by Age, Disease, and Chronic Phosphodiesterase Inhibitor Treatment

“…5 Nevertheless, children with HF from SRV demonstrate selective down-regulation of β 1 -adrenergic receptors with preserved β 2 -adrenergic receptor expression. 6 We hypothesized that the pathogenesis and regulation of cAMP and cGMP in pediatric HF are dissimilar from those of adult HF and, furthermore, that the expression profile of pediatric HF is likely distinct based on disease etiology. The molecular alterations specific to each patient population would have important implications regarding putative responses to PDE3i and other medical therapies.…”

“…1–4 Additionally, there is differential adaptation of β-adrenergic receptors and adrenergic signaling pathways in children with HF secondary to dilated cardiomyopathy (DCM) as well as single right ventricle heart disease (SRV), suggesting that both age and disease etiology may influence response to therapy. 5,6 Certainly, the treatment of pediatric HF patients comprises unique challenges, including (1) diverse etiologies of HF, (2) age-related changes, (3) treatment of a vulnerable population, and (4) a relatively low incidence of HF. Therefore, investigations into the differences between a spectrum of pediatric and adult HF populations may further our understanding of disparate mechanisms of disease as well as the variable therapeutic potential of certain medications.…”