Medina Elizabeth, Sucharov Carmen C, Nelson Penny, Miyamoto Shelley D, Stauffer Brian L
Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO.
Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
J Pediatr. 2017 Mar;182:184-189.e1. doi: 10.1016/j.jpeds.2016.11.011. Epub 2016 Nov 29.
To determine whether left ventricular assist device (LVAD) treatment in children with heart failure would result in the modification of molecular pathways involved in heart failure pathophysiology.
Forty-seven explanted hearts from children were studied (16 nonfailing control, 20 failing, and 11 failing post-LVAD implantation [F-LVAD]). Protein expression and phosphorylation states were determined by receptor binding assays and Western blots. mRNA expression was measured with real-time quantitative polymerase chain reaction. To evaluate for interactions and identify correlations, 2-way ANOVA and regression analysis were performed.
Treatment with LVAD resulted in recovery of total β-adrenergic receptor expression and β-adrenergic receptor (β-AR) in failing hearts to normal levels (β-adrenergic receptor expression : 67.2 ± 11.5 fmol/mg failing vs 99.5 ± 27.7 fmol/mg nonfailing, 104 ± 38.7 fmol/mg F-LVAD, P ≤ .01; β-AR: 52.2 ± 10.3 fmol/mg failing vs 83.0 ± 23 fmol/mg non-failing, 76.5 ± 32.1 fmol/mg F-LVAD P ≤ .03). The high levels of G protein-coupled receptor kinase-2 were returned to nonfailing levels after LVAD treatment (5.6 ± 9.0 failing vs 1.0 ± 0.493 nonfailing, 1.0 ± 1.3 F-LVAD). Interestingly, β-adrenergic receptor expression was significantly greater in F-LVAD (27.5 ± 12; P < .005) hearts compared with nonfailing (16.4 ± 6.1) and failing (15.1 ± 4.2) hearts. Phospholamban phosphorylation at serine 16 was significantly greater in F-LVAD (7.7 ± 11.7) hearts compared with nonfailing (1.0 ± 1.2, P = .02) and failing (0.8 ± 1.0, P = .01) hearts. Also, atrial natriuretic factor (0.6 ± 0.8) and brain natriuretic peptide (0.1 ± 0.1) expression in F-LVAD was significantly lower compared with failing hearts (2.8 ± 3.6, P = .01 and 0.6 ± 0.7, P = .02).
LVAD treatment in children with heart failure results in reversal of several pathologic myocellular processes, and G protein-coupled receptor kinase-2 may regulate β-AR but not β-adrenergic receptor expression in children with heart failure.
确定心力衰竭患儿接受左心室辅助装置（LVAD）治疗是否会导致参与心力衰竭病理生理学的分子途径发生改变。
对47例儿童离体心脏进行研究（16例非衰竭对照、20例衰竭以及11例LVAD植入后衰竭[F-LVAD]）。通过受体结合试验和蛋白质印迹法测定蛋白质表达和磷酸化状态。采用实时定量聚合酶链反应测量mRNA表达。为评估相互作用并确定相关性，进行了双向方差分析和回归分析。
LVAD治疗使衰竭心脏中的总β-肾上腺素能受体表达和β-肾上腺素能受体（β-AR）恢复至正常水平（β-肾上腺素能受体表达：衰竭心脏为67.2±11.5 fmol/mg，非衰竭心脏为99.5±27.7 fmol/mg，F-LVAD为104±38.7 fmol/mg，P≤0.01；β-AR：衰竭心脏为52.2±10.3 fmol/mg，非衰竭心脏为83.0±23 fmol/mg，F-LVAD为76.5±32.1 fmol/mg，P≤0.03）。LVAD治疗后，高水平的G蛋白偶联受体激酶-2恢复至非衰竭水平（衰竭心脏为5.6±9.0，非衰竭心脏为1.0±0.493，F-LVAD为1.0±1.3）。有趣的是，与非衰竭（16.4±6.1）和衰竭（15.1±4.2）心脏相比，F-LVAD心脏中的β-肾上腺素能受体表达显著更高（27.5±12；P<0.005）。与非衰竭（1.0±1.2，P=0.02）和衰竭（0.8±1.0，P=0.01）心脏相比，F-LVAD心脏中丝氨酸16位点的受磷蛋白磷酸化显著更高（7.7±11.7）。此外，与衰竭心脏相比，F-LVAD中的心房利钠因子（0.6±0.8）和脑利钠肽（0.1±0.1）表达显著更低（2.8±3.6，P=0.01和0.6±0.7，P=0.02）。
心力衰竭患儿接受LVAD治疗可导致多种病理性心肌细胞过程逆转，G蛋白偶联受体激酶-2可能调节心力衰竭患儿的β-AR，但不调节β-肾上腺素能受体表达
