The association between circulating endostatin and a disturbed circadian blood pressure pattern in patients with type 2 diabetes

<b>Background:</b> Endostatin, cleaved from collagen XVIII in the extracellular matrix, is a promising circulating biomarker for cardiovascular damage. It possesses anti-angiogenic and anti-fibrotic functions and has even been suggested to be involved in blood pressure regulation. Less is known if endostatin levels relate to circadian blood pressure patterns. In the present paper we studied the association between circulating levels of endostatin and nocturnal dipping in blood pressure. <b>Methods:</b> We used the CARDIPP-study, a cohort of middle aged, type 2 diabetics (<i>n</i> = 593, 32% women), with data on both 24-hour and office blood pressure, serum-endostatin, cardiovascular risk factors, and incident major cardiovascular events. Nocturnal dipping was defined as a &gt;10% difference between day- and night-time blood pressures. <b>Results:</b> Two-hundred four participants (34%) were classified as non-dippers. The mean endostatin levels were significantly higher in non-dippers compared to dippers (mean ± standard deviation: 62.6 ± 1.8 µg/l vs. 58.7 ± 1.6 µg/l, respectively, <i>p</i> = .007). Higher serum levels of endostatin were associated with a diminished decline in nocturnal blood pressure adjusted for age, sex, HbA1c, mean systolic day blood pressure, hypertension treatment, glomerular filtration rate, and prevalent cardiovascular disease (regression coefficient per SD increase of endostatin −0.01, 95% CI, −0.02–(−0.001), <i>p</i> = .03). Structural equation modelling analyses suggest that endostatin mediates 7% of the association between non-dipping and major cardiovascular events. <b>Conclusion:</b> We found an independent association between higher circulating levels of endostatin and a reduced difference between day- and night-time systolic blood pressure in patients with type 2 diabetes. Yet endostatin mediated only a small portion of the association between non-dipping and cardiovascular events arguing against a clinical utility of our findings.

背景：内皮抑素（Endostatin）由细胞外基质（extracellular matrix）中的胶原蛋白XVIII（collagen XVIII）裂解产生，是一种极具应用前景的心血管损伤循环生物标志物。其具备抗血管生成（anti-angiogenic）与抗纤维化（anti-fibrotic）的生物学功能，甚至被认为参与血压调控过程。目前对于内皮抑素水平与昼夜血压节律的关联仍知之甚少，本研究旨在探讨循环内皮抑素水平与血压夜间下降模式的相关性。方法：本研究使用CARDIPP队列研究的数据，该队列纳入593名中年2型糖尿病患者（女性占比32%），收集了24小时动态血压与诊室血压、血清内皮抑素水平、心血管危险因素以及新发主要心血管不良事件的相关数据。夜间血压下降模式被定义为日间与夜间血压差值超过10%。结果：共204名受试者（占比34%）被归类为非杓型血压者。非杓型组的内皮抑素平均水平显著高于杓型组（均值±标准差：62.6±1.8 μg/L vs 58.7±1.6 μg/L，p=0.007）。在校正年龄、性别、糖化血红蛋白（HbA1c）、日间平均收缩压、高血压治疗情况、肾小球滤过率（glomerular filtration rate）以及既往心血管疾病后，较高的血清内皮抑素水平与夜间血压下降幅度减小显著相关（内皮抑素每增加1个标准差的回归系数为-0.01，95%置信区间：-0.02~-0.001，p=0.03）。结构方程模型（structural equation modelling）分析显示，内皮抑素介导了非杓型血压与主要心血管不良事件之间7%的关联。结论：本研究在2型糖尿病患者中发现，循环内皮抑素水平升高与日间-夜间收缩压差减小存在独立相关性。然而内皮抑素仅介导了非杓型血压与心血管事件之间的极小部分关联，提示本研究结果尚不具备临床应用价值。