Microvascular endothelial dysfunction in mitochondrial stroke-like episodes supports use of intravenous l-arginine.
Microvascular endothelial dysfunction in mitochondrial stroke-like episodes supports use of intravenous l-arginine.
复制标题
线粒体中风样发作中的微血管内皮功能障碍支持静脉注射左旋精氨酸的使用。
DOI：
10.1016/j.ymgmr.2018.03.001
复制
发表时间：
2018
影响因子：
1.9
通讯作者：
Falk,MarniJ
中科院分区：
文献类型：
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作者：
Ganetzky,RebeccaD;Falk,MarniJ
我们感谢Finsterer和Zarrouk-Mahjoub博士[1]针对我们最近在《分子遗传学和代谢》杂志上发表的文章：“静脉注射精氨酸治疗儿科线粒体疾病急性代谢性卒中的8年回顾性分析[2]"给编辑的一封深思熟虑的信。虽然线粒体疾病中急性卒中样发作（SLE）的潜在病理生理学仍不完全清楚，但由于一氧化氮代谢改变导致的血管内皮功能障碍是至少一个子集的原因[3-9]。然而，线粒体疾病SLE是由于CNS微血管功能障碍，而不是大动脉，这解释了它们缺乏血管分布[10]。同样，我们同意，而不是大血管痉挛，代谢活动和微血管流量之间发生的病理生理不匹配。这是由异常的一氧化氮代谢介导的，并导致血流量不足，以支持神经元的代谢需求[11]。线粒体疾病SLE后经常出现细胞毒性水肿，这可能是微血管痉挛导致的缺血的结果，表现为扩散受限和表观扩散系数（ADC）降低。这些发现可能是ADC增加所致，这与血管源性水肿一致，可能代表线粒体功能障碍导致的血管内皮异常自动调节[12]。因此，短暂性血管源性水肿的发生并不与线粒体疾病SLE由血管内皮功能障碍引起的一氧化氮流量改变的假设相矛盾，最终，我们同意需要进行多中心前瞻性试验来充分评估静脉精氨酸治疗的疗效。我们希望我们的回顾性报告，支持静脉注射精氨酸作为一种低风险和潜在的有益干预措施，在急性SLE的不同遗传病因的儿科线粒体疾病，鼓励追求前瞻性临床试验。在此之前，我们的分析表明，应遵循最近的专家共识实践指南建议，考虑对发生急性SLE的线粒体疾病患者进行静脉精氨酸治疗[13]。
We appreciate the thoughtful Letter to the Editor by Drs. Finsterer and Zarrouk-Mahjoub [1] in response to our recent publication in Molecular Genetics and Metabolism:“8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease [2]”. While the underlying pathophysiology of acute stroke-like episodes (SLEs) in mitochondrial disease remains incompletely understood, vascular endothelial dysfunction due to altered nitric oxide metabolism is the cause for at least a subset [3–9]. However, mitochondrial disease SLEs are due to dysfunction of CNS microvasculature, not large arteries, explaining their absence of a vascular distribution [10]. Similarly, we agree that rather than large vessel vasospasm, a pathophysiologic mismatch occurs between metabolic activity and microvascular flow. This is mediated by abnormal nitric oxide metabolism and results in insufficient blood flow to support neuronal metabolic demand [11]. Mitochondrial disease SLEs are frequently followed by cytotoxic edema, a likely consequence of ischemia from microvascular spasm, as evidenced by diffusion restriction and decreased apparent diffusion coefficient (ADC). These findings may be proceeded by increased ADC, which is consistent with vasogenic edema and possibly represents abnormal autoregulation of the vascular endothelium due to mitochondrial dysfunction [12]. Thus, the occurrence of transient vasogenic edema is not inconsistent with the hypothesis that mitochondrial disease SLEs result from altered nitric oxide flux with vascular endothelial dysfunction.Ultimately, we agree that a multi-center prospective trial is required to fully evaluate the efficacy of intravenous arginine therapy. We hope our retrospective report, which supports intravenous arginine as a low-risk and potentially beneficial intervention at the time of acute SLEs in diverse genetic etiologies of pediatric mitochondrial disease, encourages pursuit of prospective clinical trials. Until then, our analysis suggests that recent expert consensus practice guideline recommendations should be followed regarding consideration of intravenous arginine therapy for mitochondrial disease patients who experience acute SLEs [13].