Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.
Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.
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DOI：
10.1161/circulationaha.110.004341
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发表时间：
2011-05-31
期刊：
影响因子：
37.8
通讯作者：
Pediatric Heart Network Investigators
中科院分区：
文献类型：
--
作者：
Mital S;Chung WK;Colan SD;Sleeper LA;Manlhiot C;Arrington CB;Cnota JF;Graham EM;Mitchell ME;Goldmuntz E;Li JS;Levine JC;Lee TM;Margossian R;Hsu DT;Pediatric Heart Network Investigators
我们研究了单心室婴儿中肾素-血管紧张素-醛固酮系统（RAAS）基因多态性对心室重构、生长、肾功能和对依那普利反应的影响。在依那普利的随机试验中，对单心室婴儿进行了5个基因多态性的基因分型：血管紧张素原、血管紧张素转换酶、血管紧张素II 1型受体、醛固酮合成酶和糜酶。与RAAS上调相关的等位基因被归类为风险等位基因。在两个时间点--上腔静脉连接前（pre-SCPC）和14个月大时，比较了具有≥2个纯合子风险基因型（高危）和具有<2个纯合子风险基因型（低危）的患者的心室质量、体积、体细胞生长、使用估计肾小球滤过率（eGFR）的肾功能以及对依那普利的反应。在230名试验受试者中，154人进行了基因分型：38人为高风险，116人为低风险。SCPC前两组的心室质量和体积均升高。低危组SCPC后心室质量和体积减少，eGFR增加（p<0.05），但高危组无此变化。这些反应是独立的依那普利治疗。基线时体重和身高z评分较低，14个月时高风险组的身高仍较低，尤其是接受依那普利治疗的患者（p<0.05）。RAAS上调基因型与SCPC手术后逆转重构失败、肾功能改善较少和躯体生长受损相关，后者尤其在接受依那普利治疗的患者中。RAAS基因型可以识别单心室患者的高风险亚组，这些患者不能从容量卸载手术中完全受益。有必要进行后续行动，以评估长期影响。临床Trials.gov标识符NCT 00113087
We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function and response to enalapril in infants with single ventricle. Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with RAAS upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate (eGFR), and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high-risk), and those with <2 homozygous risk genotypes (low-risk) at two time points - before the superior-cavopulmonary-connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: 38 were high-risk, 116 were low-risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and eGFR increased after SCPC in the low-risk (p<0.05) but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline and height remained lower in the high-risk group at 14 months especially in those receiving enalapril (p<0.05). RAAS-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. RAAS genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume unloading surgery. Follow-up is warranted to assess longterm impact. Clinical Trials.gov Identifier NCT00113087