Jin Xuyan, Morais Andreia, Imai Takahiko, Lamb Jessica, Nagarkatti Karisma, Boisserand Ligia S B, Beatty Hannah, Sansing Lauren H, Khan Mohammad B, Dhandapani Krishnan, Kamat Pradip, Hess David C, Patel Rakesh B, Kumskova Mariia, Chauhan Anil K, McCullough Louise D, Aronowski Jaroslaw, Leira Enrique C, Shi Yanrong, Avery Brooklyn D, Koehler Raymond C, Lyden Patrick D, Ayata Cenk
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown. (X.J., A.M., T.I., C.A.).
Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.N., P.D.L.).
Stroke. 2025 May 21. doi: 10.1161/STROKEAHA.125.051235.
The SPAN (Stroke Preclinical Assessment Network) is a confirmatory trial platform to test the efficacy and safety of candidate cerebroprotective interventions in acute stroke. As the largest multicenter preclinical stroke trial to date, the SPAN1 trial (first SPAN) prospectively captured many biological and procedural variables, revealing a high degree of heterogeneity introduced by the multicenter approach that may impact stroke outcomes. Here, we examined the biological and procedural predictors of tissue and neurological outcomes after focal cerebral ischemic stroke in rats.
SPAN1 enrolled and randomized 698 rats to various active treatment arms or controls. Rats were subjected to transient middle cerebral artery occlusion for 60 (spontaneously hypertensive rats) or 120 minutes (young, healthy Sprague-Dawley rats) and followed for 1 month. Nine biological and procedural independent variables (sex, weight, strain, intervention arm, site, endovascular filament silicone tip coating characteristics, anesthesia duration, and intervention protocol) and 5 dependent outcome variables (weight loss, 4-point neuroscore, corner test, infarct volume, and mortality) were captured. Multivariable regression was used to identify independent predictors of each outcome readout and determine their effect sizes.
Spontaneously hypertensive rats exhibited larger infarcts than Sprague-Dawley rats, particularly among females. Neuroscores were also worse in spontaneously hypertensive rats. Prolonged anesthesia exposure was associated with smaller cortical and hippocampal infarcts. Filament thickness and length showed a complex association with different regional infarct volumes, neuroscores, weight loss, and corner test outcomes. Mortality was worse among females. Bivariate analysis of dependent variables revealed moderate correlations among the tissue and neurological outcomes.
Using the large and multicenter, prospective SPAN1 dataset, our multivariable analyses identified several predictors influencing rat middle cerebral artery occlusion outcomes and refuted others previously reported. Investigators should consider whether biological and procedural predictors identified herein should be standardized, accounted for, or stratified during subject allocation to decrease variability and avoid confounders in future multicenter preclinical trials.
卒中临床前评估网络（SPAN）是一个验证性试验平台，用于测试候选脑保护干预措施在急性卒中中的疗效和安全性。作为迄今为止最大的多中心临床前卒中试验，SPAN1试验（首个SPAN试验）前瞻性地收集了许多生物学和操作变量，揭示了多中心方法引入的高度异质性，这可能会影响卒中结局。在此，我们研究了大鼠局灶性脑缺血性卒中后组织和神经学结局的生物学和操作预测因素。
SPAN1纳入698只大鼠并将其随机分为不同的活性治疗组或对照组。对大鼠进行60分钟（自发性高血压大鼠）或120分钟（年轻、健康的Sprague-Dawley大鼠）的短暂大脑中动脉闭塞，并随访1个月。收集了9个生物学和操作独立变量（性别、体重、品系、干预组、部位、血管内细丝硅胶尖端涂层特征、麻醉持续时间和干预方案）和5个相关结局变量（体重减轻、4分神经评分、转角试验、梗死体积和死亡率）。采用多变量回归来确定每个结局读数的独立预测因素，并确定其效应大小。
自发性高血压大鼠的梗死灶比Sprague-Dawley大鼠更大，尤其是在雌性大鼠中。自发性高血压大鼠的神经评分也更差。长时间麻醉与较小的皮质和海马梗死灶相关。细丝厚度和长度与不同区域的梗死体积、神经评分、体重减轻和转角试验结果显示出复杂的关联。雌性大鼠的死亡率更高。对相关变量的双变量分析显示，组织和神经学结局之间存在中度相关性。
利用大型多中心前瞻性SPAN1数据集，我们的多变量分析确定了几个影响大鼠大脑中动脉闭塞结局的预测因素，并反驳了其他先前报道的因素。研究人员应考虑在受试者分配过程中，本文确定的生物学和操作预测因素是否应标准化、考虑或分层，以减少变异性并避免在未来的多中心临床前试验中出现混杂因素。
