Grosse Gerrit M, Blume Nicole, Abu-Fares Omar, Götz Friedrich, Ernst Johanna, Leotescu Andrei, Gabriel Maria M, van Gemmeren Till, Worthmann Hans, Lichtinghagen Ralf, Imker Rabea, Falk Christine S, Weissenborn Karin, Schuppner Ramona, de Buhr Nicole
Department of Neurology (G.M.G., N.B., J.E., A.L., M.M.G., T.v.G., H.W., K.W., R.S.), Hannover Medical School, Germany.
Institute of Diagnostic and Interventional Neuroradiology (O.A.-F., F.G.), Hannover Medical School, Germany.
Stroke. 2022 Apr;53(4):1235-1244. doi: 10.1161/STROKEAHA.121.036299. Epub 2022 Jan 7.
Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke.
Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset.
Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001-12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006-45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237-0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity.
The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.
游离DNA（cfDNA）和内源性脱氧核糖核酸酶活性是相反的介质，可能影响急性缺血性卒中后的炎症反应。在这项队列研究中，我们调查了这些标志物、循环炎症介质与急性卒中患者临床病程（包括卒中相关感染[SAI]的发生）之间的关系。
2018年3月至2019年8月，在汉诺威医学院前瞻性招募了92例因大血管闭塞导致卒中并接受机械取栓术的患者。在机械取栓术前及术后7天采集静脉血，检测脱氧核糖核酸酶活性、cfDNA、损伤相关分子模式和循环细胞因子。再灌注状态分为充分/不充分。90天后使用改良Rankin量表评估临床结局，评分3至6分被认为是不良结局。为验证关于SAI的研究结果，纳入了另一个卒中队列（n = 92），采集卒中发作后24小时内的血液。
临床结局不良的患者cfDNA浓度较高。在调整混杂因素（埃森卒中风险评分、美国国立卫生研究院卒中量表评分和性别）后，7天时的cfDNA与临床结局尤其是死亡率独立相关（调整后的优势比：3.485 [95% CI，1.001 - 12.134]和调整后的优势比：9.585 [95% CI，2.006 - 45.790]）。未发现再灌注状态与cfDNA或脱氧核糖核酸酶活性之间存在关联。虽然cfDNA浓度呈正相关，但脱氧核糖核酸酶活性与不同的生物标志物呈负相关。发生SAI的患者基线脱氧核糖核酸酶活性低于未发生SAI的患者。在调整混杂因素后，这种关联得到证实（调整后的优势比：0.447 [95% CI，0.237 - 0.844]）。在队列2中，卒中严重程度越高，发生SAI和未发生SAI的患者之间脱氧核糖核酸酶活性的差异往往越大。
急性卒中中内源性脱氧核糖核酸酶活性与cfDNA的相互作用带来了有趣的新型诊断和潜在治疗方法。我们证实了cfDNA与大血管闭塞性卒中后不良临床病程的独立关联。本研究首次提供证据表明，内源性脱氧核糖核酸酶活性降低是重症卒中后发生SAI的危险因素。
