Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects.
Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects.
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DOI：
10.1097/pcc.0000000000001275
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发表时间：
2017-10
期刊：
影响因子：
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通讯作者：
Fineman JR
中科院分区：
文献类型：
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作者：
Black SM;Field-Ridley A;Sharma S;Kumar S;Keller RL;Kameny R;Maltepe E;Datar SA;Fineman JR
先天性心脏病（CHD）伴肺血流量（PBF）增加导致进行性肺血管内皮功能障碍和相关的围手术期发病率增加。利用我们的绵羊CHD模型与PBF增加，我们以前已经证明了进行性内皮功能障碍与破坏肉毒碱稳态，线粒体功能障碍，减少一氧化氮（NO）信号，并增强活性氧（ROS）的产生。然而，尚未研究CHD患者这些参数的潜在变化。本研究的目的是检验这一假设，即PBF增加的儿童将有证据表明肉毒碱稳态改变，线粒体功能障碍，NO水平降低，ROS生成增加。一项前瞻性单中心队列研究A三级护理CICU/PICU从18名患有与PBF增加相关的CHD（室间隔缺损，VSD）的患者、20名患有CHD但没有PBF增加的患者（法洛四联症，TOF）和10名没有心脏病的患者（对照）获得动脉血样。血浆水平的总肉碱（TC），游离肉碱（FC），酰基肉碱（AC）和乳酸丙酮酸比，线粒体功能的指标，进行了测定和比较。此外，超氧化物和过氧化氢的水平进行了测定和比较，室间隔缺损患者和对照组。使用非配对t检验和ANOVA进行统计分析。VSD组的基线AC水平（25.7 ± 13 vs. 12.7 ± 8.3，P<0.05）、AC：FC比值（0.8 ± 0.1 vs. 0.3 ± 0.05，P<0.05）和乳酸/丙酮酸比值（27.5 ± 3.8 vs. 11.1 ± 4.1，P<0.05）均高于TOF组; TOF组与对照组之间无差异。VSD患者的超氧化物和H2 O2水平也高于对照组，而NOx水平低于TOF和对照组（P<0.05）。这些数据表明，从VSD的PBF增加的结果在改变肉毒碱和线粒体的稳态，减少NO信号，并增加ROS的生产。这些数据是一致的，我们的动物数据表明，改变肉毒碱体内平衡的结果在线粒体功能障碍，增加活性氧的产生，并减少生物可利用的NO。由于破坏肉毒碱代谢可能会导致内皮功能障碍，补充肉毒碱可能会减弱内皮功能障碍与PBF增加，并值得进一步调查。
Congenital heart disease (CHD) with increased pulmonary blood flow (PBF) results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Utilizing our ovine model of CHD with increased PBF, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide (NO) signaling, and enhanced reactive oxygen species (ROS) generation. However, potential alterations in these parameters in patients with CHD have not been investigated. The objective of this study was to test the hypothesis that children with increased PBF will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased NO levels, and increased ROS generation. A prospective single center cohort study A tertiary care CICU/PICU Arterial blood samples from 18 patients with CHD associated with increased PBF (ventricular septal defect, VSD), 20 with CHD without increased PBF (tetralogy of Fallot, TOF), and 10 without heart disease (controls) were obtained. Plasma levels of total carnitine (TC), free carnitine (FC), acylcarnitine (AC); and lactate-to-pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with VSD and controls. Statistical analysis was performed using an unpaired t-test and ANOVA. Baseline AC levels (25.7 ± 13 vs. 12.7 ± 8.3, P<0.05), the AC:FC ratio (0.8 ± 0.1 vs. 0.3 ± 0.05, P<0.05), and the lactate/pyruvate ratio were higher in VSD (27.5 ± 3.8 vs. 11.1 ± 4.1, P<0.05) than TOF; there were no differences between TOF and control. Superoxide and H2O2 levels were also higher in VSD compared to controls, and NOx levels were lower in VSD patients compared to TOF and controls (P<0.05). These data suggest that increased PBF from VSD results in altered carnitine and mitochondrial homeostasis, decreased NO signaling, and increased ROS production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased ROS production, and decreased bioavailable NO. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased PBF and warrants further investigation.