Sex-related differences in age-associated downregulation of human ventricular myocardial ß1-adrenergic receptors.

BACKGROUND: With increasing age, human ventricular myocardium exhibits selective downregulation of ß1-adrenergic receptors (ß1-ARs). We tested the hypothesis that sex differences exist in age-related changes in ß1-ARs. METHODS: Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy. ß1-AR and ß2-AR densities, the frequency of ß1-AR389 gene variants, and ß-AR function were determined. RESULTS: Sex had a marked effect on the age-related decrease in ß1-ARs. Female LVs had more pronounced downregulation (by 42% [p < 0.001] vs 22% [p = 0.21] in 31 male LVs) comparing the youngest (average age, 15.3 ± 5.5 years) to the oldest (average age, 50.8 ± 9.1 years) sub-groups. On regression analyses, female LVs exhibited a closer relationship between ß1-AR density and age (r = -0.78, p <0.001 vs r = -0.46, p = 0.009 in males), with a second-degree polynomial yielding the best fit. There was no statistically significant relationship of ß1-ARs to age in female or male idiopathic dilated cardiomyopathy LVs. CONCLUSIONS: Sex affects age-related ß-AR downregulation in normal human ventricles, with females exhibiting more profound decreases with increasing age. The curvilinear relationship between age and receptor density that plateaus around age 40 in women suggests an effect of sex hormones on ß1-AR expression in the human heart.

Circulating microRNA as a biomarker for recovery in pediatric dilated cardiomyopathy.

BACKGROUND: MicroRNAs (miRNAs) are short regulatory RNAs that control gene expression through interacting with the 3'UTR of target messenger RNAs. The purpose of this study was to determine if circulating miRNAs are useful biomarkers of outcome in children with dilated cardiomyopathy (DCM). METHODS: An array for 754 miRNAs and real time polymerase chain reaction confirmation of select miRNAs were performed. Serum from 55 children <18 years old with DCM was analyzed. Samples were drawn from all patients with DCM when undergoing heart transplant evaluation and/or at the time of transplantation. Patients with DCM were categorized based on when their blood was drawn (Pre-Transplant or Transplant) and outcome (Transplant/died or Recovered). RESULTS: Two miRNAs were significantly up-regulated (hsa-miR-155 and hsa-miR-636) and 2 miRNAs were down-regulated (hsa-miR-646 and hsa-miR-639) in patients with DCM who were transplanted or died compared with patients with DCM who recovered their ventricular function. Receiver operator curves, performed for differences in any 1 of these 4 differentially regulated miRNAs in patients who were transplanted or died compared with patients who recovered, resulted in an area under the receiver operating characteristic curve of 0.875 for the Pre-Transplant blood draw time point and an area under the receiver operating characteristic curve of 0.93 for the day of Transplant time point. CONCLUSIONS: We identified specific miRNAs that are differentially regulated between children with DCM who need a transplant compared with children with DCM who recover. A unique biomarker signature of miRNAs that are specific to children with DCM who have the potential to recover would be valuable in risk stratification of this challenging patient population.

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

BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the ß-adrenergic receptor (ß-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 ß-AR due to down-regulation of ß1-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 ß-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 ß1-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 ß-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.