Martinez-Aguayo Alejandro, Campino Carmen, Baudrand Rene, Carvajal Cristian A, García Hernán, Aglony Marlene, Bancalari Rodrigo, García Lorena, Loureiro Carolina, Vecchiola Andrea, Tapia-Castillo Alejandra, Valdivia Carolina, Sanhueza Sebastian, Fuentes Cristobal A, Lagos Carlos F, Solari Sandra, Allende Fidel, Kalergis Alexis M, Fardella Carlos E
aDivision of Pediatrics bDepartment of Endocrinology cMillennium Institute on Immunology and Immunotherapy, Department of Molecular Genetics and Microbiology, Pontificia Universidad Católica de Chile dAdvanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, University of Chile eStudent, School of Medicine, Pontificia Universidad Católica de Chile fFacultad de Ciencia, Universidad San Sebastián gDepartment of Clinical Laboratories, Facultad de Medicina hDepartment of Celular and Molecular Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile *Alejandro Martinez-Aguayo and Carmen Campino contributed equally to this work.
J Hypertens. 2016 Sep;34(9):1808-14. doi: 10.1097/HJH.0000000000001017.
To identify novel biomarkers associated with pediatric primary hypertension.
We recruited 350 participants (4-16 years). Anthropometric parameters and aldosterone, plasma renin activity, cortisol, cortisone, Homeostasis Model Assessment Insulin Resistance (HOMA-IR), high-sensitivity C-reactive protein, adiponectin, IL-6, plasminogen activator inhibitor type 1 levels and matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9 and MMP-2) activities were measured. Genomic DNA was isolated. Patients with altered glucose metabolism, severe obesity [BMI-SD score (BMI-SDS) > 2.5], renovascular disease, primary aldosteronism and apparent mineralocorticoid excess syndrome were excluded.
In selected participants (n = 320), SBP was positively correlated with BMI-SDS (r = 0.382, P < 0.001), HOMA-IR (r = 0.211, P < 0.001), MMP-9 activity (r = 0.215, P < 0.001) and the cortisol/cortisone ratio (r = 0.231, P < 0.001). DBP showed similar correlations with these variables. No correlation was observed with aldosterone or plasma renin activity. Participants were categorized as hypertensive (n = 59) or nonhypertensive (n = 261). In the univariate analysis, hypertensive patients had higher BMI-SDS (P < 0.001), HOMA-IR (P < 0.001), high-sensitivity C-reactive protein (P < 0.001), MMP-9 activity (P < 0.001), plasminogen activator inhibitor type 1 (P < 0.001) and cortisol/cortisone ratio (P < 0.001) than nonhypertensive patients. Multiple regression analysis showed that the variables that remained associated with hypertension were higher BMI-SDS [odds ratio (OR) = 3.74; 95% confidence interval (CI) = 1.84-7.58], a higher cortisol/cortisone ratio (OR = 3.92; 95% CI = 1.98-7.71) and increased MMP-9 activity (OR = 4.23; 95% CI = 2.15-8.32).
We report that MMP-9 activity and the cortisol/cortisone ratio were higher in pediatric primary hypertensive patients, and these associations were independent of the effect of obesity. The potential role of these novel biomarkers in predicting hypertension risk and blood pressure regulation warrants further investigation.
识别与儿童原发性高血压相关的新型生物标志物。
我们招募了350名参与者（4至16岁）。测量了人体测量参数以及醛固酮、血浆肾素活性、皮质醇、可的松、稳态模型评估胰岛素抵抗（HOMA-IR）、高敏C反应蛋白、脂联素、白细胞介素-6、纤溶酶原激活物抑制剂1水平以及基质金属蛋白酶-9和基质金属蛋白酶-2（MMP-9和MMP-2）活性。分离了基因组DNA。排除了糖代谢改变、重度肥胖[BMI标准差评分（BMI-SDS）>2.5]、肾血管疾病、原发性醛固酮增多症和表观盐皮质激素过多综合征患者。
在选定的参与者（n = 320）中，收缩压与BMI-SDS呈正相关（r = 0.382，P < 0.001）、与HOMA-IR呈正相关（r = 0.211，P < 0.001）、与MMP-9活性呈正相关（r = 0.215，P < 0.001）以及与皮质醇/可的松比值呈正相关（r = 0.231，P < 0.001）。舒张压与这些变量呈现相似的相关性。未观察到与醛固酮或血浆肾素活性的相关性。参与者被分为高血压组（n = 59）或非高血压组（n = 261）。在单因素分析中，高血压患者的BMI-SDS更高（P < 0.001）、HOMA-IR更高（P < 0.00）、高敏C反应蛋白更高（P < 0.001）、MMP-9活性更高（P < 0.001）、纤溶酶原激活物抑制剂1更高（P < 0.001）以及皮质醇/可的松比值更高（P < 0.001）。多因素回归分析显示，与高血压仍相关的变量为更高的BMI-SDS[比值比（OR）= 3.74；95%置信区间（CI）= 1.84 - 7.58]、更高的皮质醇/可的松比值（OR = 3.92；95% CI = 1.98 - 7.71）以及升高的MMP-9活性（OR = 4.23；95% CI = 2.15 - 8.32）。
我们报告称，儿童原发性高血压患者的MMP-9活性和皮质醇/可的松比值更高，且这些关联独立于肥胖的影响。这些新型生物标志物在预测高血压风险和血压调节中的潜在作用值得进一步研究。
