Brookes Rebecca L, Crichton Siobhan, Wolfe Charles D A, Yi Qilong, Li Linxin, Hankey Graeme J, Rothwell Peter M, Markus Hugh S
From the Stroke Research Group, Clinical Neurosciences, University of Cambridge, United Kingdom (R.L.B., H.S.M.); Division of Health and Social Care Research, Faculty of Life Sciences and Medicine, King's College London, United Kingdom (S.C., C.D.A.W.); National Epidemiology and Surveillance, Canadian Blood Services, Ottawa, Ontario (Q.Y.); School of Medicine and Pharmacology, The University of Western Australia, Perth (G.J.H.); Department of Neurology, Sir Charles Gairdner Hospital, Perth, Australia (G.J.H.); Western Australian Neuroscience Research Institute, Perth (G.J.H.); and Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom (L.L., P.M.R.).
Stroke. 2018 Jan;49(1):54-61. doi: 10.1161/STROKEAHA.117.016674. Epub 2017 Dec 15.
A variant in the histone deacetylase 9 () gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate.
Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression.
A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; =0.003).
These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.
组蛋白去乙酰化酶9（HDAC9）基因的一个变异与大动脉性卒中相关。因此，抑制HDAC9可能为缺血性卒中提供一种新的二级预防治疗方法。抗癫痫药物丙戊酸钠（SVA）是HDAC9的非特异性抑制剂。我们测试了缺血性卒中后给予SVA治疗是否与降低复发性卒中发生率相关。
数据来自3项招募既往有卒中或短暂性脑缺血发作患者并进行长期随访的前瞻性研究：南伦敦卒中登记研究、预防卒中的维生素研究以及牛津血管研究。使用生存分析和Cox回归，将接受SVA治疗的患者与接受SVA以外其他抗癫痫药物治疗的患者进行比较。
共纳入11949例确诊缺血性事件的患者。服用SVA的患者（168例中有17例）复发性卒中发生率低于服用其他抗癫痫药物的患者（530例中有105例；对数秩生存分析P=0.002）。在Cox回归分析中，在控制潜在混杂因素后，SVA仍与卒中发生率降低相关（风险比=0.44；95%置信区间：0.3 - 0.7；P=0.002）。将服用SVA的患者与所有未服用SVA的病例进行比较时，得到了类似结果（Cox回归分析，风险比=0.47；95%置信区间：0.29 - 0.77；P=0.003）。
这些结果表明，尽管在本研究设计中我们不能排除残余混杂因素，但接触HDAC抑制剂SVA可能与较低的复发性卒中风险相关。这支持了HDAC9在缺血性卒中发病机制中很重要的假说，并且其被SVA或更特异性的HDAC9抑制剂抑制，作为预防复发性缺血性卒中的一种治疗方法值得评估。
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