Miyamoto Shelley D, Stauffer Brian L, Polk Jeremy, Medway Allen, Friedrich Matthew, Haubold Kurt, Peterson Valencia, Nunley Karin, Nelson Penny, Sobus Rebecca, Stenmark Kurt R, Sucharov Carmen C
Department of Pediatrics and Children's Hospital Colorado, Aurora, Colorado.
Division of Cardiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Division of Cardiology, Denver Health and Hospital Authority, Denver, Colorado.
J Heart Lung Transplant. 2014 Aug;33(8):785-93. doi: 10.1016/j.healun.2014.02.030. Epub 2014 Mar 5.
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).
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.
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.
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.
本研究的目的是确定左心发育不全综合征（HLHS）患儿体循环右心室（RV）中发生的心肌细胞变化以及β-肾上腺素能受体（β-AR）系统的适应性变化。
本研究使用了HLHS患儿和无心力衰竭对照组患儿的离体心脏。HLHS患者分为两组：“代偿性”（C-HLHS）组，即列入初次移植名单且右心室功能正常、无心力衰竭症状的婴儿；“失代偿性”（D-HLHS）组，即手术姑息治疗失败后因右心室衰竭和/或难治性蛋白丢失性肠病或塑形支气管炎而列入移植名单的患者。
与无心力衰竭的对照右心室相比，HLHS右心室肌浆网钙-腺苷三磷酸酶2a和α-肌球蛋白重链（MHC）基因表达降低，由于β1-AR下调导致总β-AR减少，环磷酸腺苷水平保持不变，钙/钙调蛋白依赖性蛋白激酶II（CaMKII）活性增加。仅在C-HLHS组中，心房利钠肽表达增加。D-HLHS组患者的独特表现为β-MHC增加、α-MHC蛋白表达减少（MHC亚型转换）、腺苷酸环化酶5表达增加以及受磷蛋白上CaMK靶位点苏氨酸17的磷酸化增加。
与无心力衰竭的对照右心室相比，HLHS右心室具有异常的心肌基因表达模式、β1-AR下调、环磷酸腺苷水平保持不变以及CaMKII活性增加。仅在D-HLHS组中存在MHC亚型转换、腺苷酸环化酶5增加以及受磷蛋白苏氨酸17磷酸化增加。尽管HLHS中异常基因表达和β-AR系统变化先于临床上明显的心室衰竭出现，但HLHS且手术姑息治疗失败的患者会出现额外的独特适应性变化。
