急性缺血性脑卒中后自主神经功能障碍导致的多系统并发症的研究进展

doi:10.3969/j.issn.1674-8115.2024.07.015

摘要/Abstract

摘要：

脑血管疾病严重危害人类健康。最新流行病学资料显示，脑卒中为全球成人死亡及致残的主要原因之一。急性缺血性卒中（acute ischemic stroke，AIS）是由大脑局部血液循环障碍引起，占脑卒中的80%以上，为最常见的卒中类型。由于AIS对大脑皮质的广泛损害或病变直接累及自主神经中枢及通路，导致交感神经系统与副交感神经系统的平衡被打破（表现出以交感神经系统激活为主）。因此，交感与副交感神经系统下游所支配的靶器官因其分泌的神经递质的影响，产生一系列的系统性并发症（如心脏并发症、卒中相关感染、胃肠道并发症、急性肾损伤、代谢改变以及性功能障碍等）。反之，那些系统性的病理改变可能影响AIS的进展，从而加剧脑损伤或直接导致患者死亡。针对自主神经系统失衡的治疗可以起到减少并发症、改善AIS预后的作用。该文综述了AIS后自主神经功能障碍的全身性效应和其机制，为AIS的治疗及其系统并发症的干预提供参考。

关键词: 急性缺血性脑卒中, 自主神经系统, 并发症, 交感神经系统, 副交感神经系统

Abstract:

Cerebrovascular diseases pose a serious threat to human health. According to the latest epidemiological data, stroke is one of the leading causes of death and disability among adults worldwide. Acute ischemic stroke (AIS), which is caused by local circulatory disorders in the brain, accounts for over 80% of all strokes and is the most common type of stroke. Due to extensive damage to the cerebral cortex or direct involvement of the autonomic nerve centers and pathways caused by AIS, the balance between the sympathetic and parasympathetic nervous systems is disturbed (with a predominance of sympathetic activation). Therefore, the organs targeted by the downstream pathways of the sympathetic and parasympathetic nervous systems are affected by the neurotransmitters they secrete, resulting in a range of systemic complications (such as cardiac complications, stroke-related infections, gastrointestinal complications, acute kidney injury, metabolic changes, and sexual dysfunction). These systemic pathological changes, in turn, affect the progression of AIS, thereby exacerbating brain damage or directly leading to patient death. Treatments targeting imbalances in the autonomic nervous system may play a role in reducing complications and improving the prognosis of AIS. This article reviews the systemic effects of autonomic dysfunction following AIS and its mechanisms, providing insights for the treatment of AIS and intervention of systemic complications.

Key words: acute ischemic stroke (AIS), autonomic nervous system, complication, sympathetic nervous system (SNS), parasympathetic nervous system (PNS)

中图分类号:

R743.3

钟佳琪, 曹雯霏, 周慧中, 杨嘉君. 急性缺血性脑卒中后自主神经功能障碍导致的多系统并发症的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(7): 928-934.

ZHONG Jiaqi, CAO Wenfei, ZHOU Huizhong, YANG Jiajun. Research progress in systemic complications induced by autonomic dysfunction after acute ischemic stroke[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(7): 928-934.

参考文献 61

1	BARTHELS D, DAS H. Current advances in ischemic stroke research and therapies[J]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866(4): 165260.
2	GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990‒2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet Neurol, 2019, 18(5): 459-480.
3	LI J, ZHANG P, CHEN H, et al. Major complications associated with unfavorable outcome in right-sided large hemisphere infarctions: a single-center study[J]. Brain Behav, 2023, 13(7): e3095.
4	XIONG L, TIAN G, LEUNG H, et al. Autonomic dysfunction predicts clinical outcomes after acute ischemic stroke: a prospective observational study[J]. Stroke, 2018, 49(1): 215-218.
5	ORGIANELIS I, MERKOURIS E, KITMERIDOU S, et al. Exploring the utility of autonomic nervous system evaluation for stroke prognosis[J]. Neurol Int, 2023, 15(2): 661-696.
6	WANG Y Y, LIN S Y, CHUANG Y H, et al. Activation of hepatic inflammatory pathways by catecholamines is associated with hepatic insulin resistance in male ischemic stroke rats[J]. Endocrinology, 2014, 155(4): 1235-1246.
7	AKIL E, TAMAM Y, AKIL M A, et al. Identifying autonomic nervous system dysfunction in acute cerebrovascular attack by assessments of heart rate variability and catecholamine levels[J]. J Neurosci Rural Pract, 2015, 6(2): 145-150.
8	XIONG L, LEUNG H H, CHEN X Y, et al. Comprehensive assessment for autonomic dysfunction in different phases after ischemic stroke[J]. Int J Stroke, 2013, 8(8): 645-651.
9	BALLA H Z, CAO Y, STRÖM J O. Effect of β-blockers on stroke outcome: a meta-analysis[J]. Clin Epidemiol, 2021, 13: 225-236.
10	BUCKLEY B J R, HARRISON S L, HILL A, et al. Stroke-heart syndrome: incidence and clinical outcomes of cardiac complications following stroke[J]. Stroke, 2022, 53(5): 1759-1763.
11	VORNHOLZ L, NIENHAUS F, GLIEM M, et al. Acute heart failure after reperfused ischemic stroke: association with systemic and cardiac inflammatory responses[J]. Front Physiol, 2021, 12: 782760.
12	HACHINSKI V C, WILSON J X, SMITH K E, et al. Effect of age on autonomic and cardiac responses in a rat stroke model[J]. Arch Neurol, 1992, 49(7): 690-696.
13	WINDER K, VILLEGAS MILLAR C, SIEDLER G, et al. Acute right insular ischaemic lesions and poststroke left ventricular dysfunction[J]. Stroke Vasc Neurol, 2023, 8(4): 301-306.
14	HIESTAND T, HÄNGGI J, KLEIN C, et al. Takotsubo syndrome associated with structural brain alterations of the limbic system[J]. J Am Coll Cardiol, 2018, 71(7): 809-811.
15	CHEN Z L, VENKAT P, SEYFRIED D, et al. Brain-heart interaction: cardiac complications after stroke[J]. Circ Res, 2017, 121(4): 451-468.
16	ROTH S, SINGH V, TIEDT S, et al. Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke[J]. Sci Transl Med, 2018, 10(432): eaao1313.
17	CHEN X P, LIANG X X, ZHANG J, et al. Serum calcium levels and in-hospital infection risk in patients with acute ischemic stroke[J]. Neuropsychiatr Dis Treat, 2022, 18: 943-950.
18	TEH W H, SMITH C J, BARLAS R S, et al. Impact of stroke-associated pneumonia on mortality, length of hospitalization, and functional outcome[J]. Acta Neurol Scand, 2018, 138(4): 293-300.
19	WANG Q, WU Z Y, TANG H L, et al. The efficacy and safety of prophylactic antibiotics for post-acute stroke infection: a systematic review and meta-analysis[J]. Br J Clin Pharmacol, 2023, 89(3): 946-955.
20	KLEIN R L, WILSON S P, DZIELAK D J, et al. Opioid peptides and noradrenaline co-exist in large dense-cored vesicles from sympathetic nerve[J]. Neuroscience, 1982, 7(9): 2255-2261.
21	ZHOU M M, LUO Q, XU Y N. As an inhibitor of norepinephrine release, dexmedetomidine provides no improvement on stroke-associated pneumonia in mice[J]. Front Pharmacol, 2023, 14: 1203646.
22	MCCULLOCH L, SMITH C J, MCCOLL B W. Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke[J]. Nat Commun, 2017, 8: 15051.
23	WANG J P, YU L, JIANG C, et al. Cerebral ischemia increases bone marrow CD4⁺CD25⁺FoxP3⁺ regulatory T cells in mice via signals from sympathetic nervous system[J]. Brain Behav Immun, 2015, 43: 172-183.
24	ELENKOV I J, WILDER R L, CHROUSOS G P, et al. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system[J]. Pharmacol Rev, 2000, 52(4): 595-638.
25	STANLEY D, MASON L J, MACKIN K E, et al. Translocation and dissemination of commensal bacteria in post-stroke infection[J]. Nat Med, 2016, 22(11): 1277-1284.
26	TUZ A A, HASENBERG A, HERMANN D M, et al. Ischemic stroke and concomitant gastrointestinal complications: a fatal combination for patient recovery[J]. Front Immunol, 2022, 13: 1037330.
27	LI J X, YUAN M G, LIU Y F, et al. Incidence of constipation in stroke patients: a systematic review and meta-analysis[J]. Medicine (Baltimore), 2017, 96(25): e7225.
28	DU W L, ZHAO X Q, WANG Y L, et al. Gastrointestinal bleeding during acute ischaemic stroke hospitalisation increases the risk of stroke recurrence[J]. Stroke Vasc Neurol, 2020, 5(2): 116-120.
29	DUAN H Y, CAI X Q, LUAN Y Y, et al. Regulation of the autonomic nervous system on intestine[J]. Front Physiol, 2021, 12: 700129.
30	YI J H, CHUN M H, KIM B R, et al. Bowel function in acute stroke patients[J]. Ann Rehabil Med, 2011, 35(3): 337-343.
31	CHENG J F, LI L D, XU F, et al. Poststroke constipation is associated with impaired rectal sensation[J]. Am J Gastroenterol, 2020, 115(1): 105-114.
32	SONG J R, CHEN W J, YE W. Stroke and the risk of gastrointestinal disorders: a Mendelian randomization study[J]. Front Neurol, 2023, 14: 1131250.
33	KAWAKUBO K, IBAYASHI S, NAGAO T, et al. Brain ischemia and gastric mucosal damage in spontaneously hypertensive rats: the role of arterial vagal adrenoceptors[J]. Dig Dis Sci, 1996, 41(12): 2383-2391.
34	QURESHI A I, ASLAM H, ZAFAR W, et al. Acute kidney injury in acute ischemic stroke patients in clinical trials[J]. Crit Care Med, 2020, 48(9): 1334-1339.
35	CAI Y Y, LU X W, CHENG X, et al. Increased renal dysfunction, apoptosis, and fibrogenesis through sympathetic hyperactivity after focal cerebral infarction[J]. Transl Stroke Res, 2022, 13(4): 641-651.
36	KHALID F, YANG G L, MCGUIRE J L, et al. Autonomic dysfunction following traumatic brain injury: translational insights[J]. Neurosurg Focus, 2019, 47(5): E8.
37	KIM J, PADANILAM B J. Renal denervation prevents long-term sequelae of ischemic renal injury[J]. Kidney Int, 2015, 87(2): 350-358.
38	MESSERER D A C, HALBGEBAUER R, NILSSON B, et al. Immunopathophysiology of trauma-related acute kidney injury[J]. Nat Rev Nephrol, 2021, 17(2): 91-111.
39	MATZ K, TUOMILEHTO J, TEUSCHL Y, et al. Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke[J]. Cardiovasc Diabetol, 2020, 19(1): 204.
40	WANG Y, JIANG G N, ZHANG J, et al. Blood glucose level affects prognosis of patients who received intravenous thrombolysis after acute ischemic stroke? A meta-analysis[J]. Front Endocrinol (Lausanne), 2023, 14: 1120779.
41	SYKORA M, DIEDLER J, POLI S, et al. Association of non-diabetic hyperglycemia with autonomic shift in acute ischaemic stroke[J]. Eur J Neurol, 2012, 19(1): 84-90.
42	LIN S Y, WANG Y Y, CHANG C Y, et al. Effects of β-adrenergic blockade on metabolic and inflammatory responses in a rat model of ischemic stroke[J]. Cells, 2020, 9(6): 1373.
43	ZHAO Z, WANG L, GAO W L, et al. A central catecholaminergic circuit controls blood glucose levels during stress[J]. Neuron, 2017, 95(1): 138-152.e5.
44	WANG Y Y, LIN S Y, CHUANG Y H, et al. Adipose proinflammatory cytokine expression through sympathetic system is associated with hyperglycemia and insulin resistance in a rat ischemic stroke model[J]. Am J Physiol Endocrinol Metab, 2011, 300(1): E155-E163.
45	RAJE V, AHERN K W, MARTINEZ B A, et al. Adipocyte lipolysis drives acute stress-induced insulin resistance[J]. Sci Rep, 2020, 10(1): 18166.
46	STRATTON H, SANSOM J, BROWN-MAJOR A, et al. Interventions for sexual dysfunction following stroke[J]. Cochrane Database Syst Rev, 2020, 5(5): CD011189.
47	CHEUNG R T F. Sexual functioning in Chinese stroke patients with mild or no disability[J]. Cerebrovasc Dis, 2002, 14(2): 122-128.
48	PISTOIA F, GOVONI S, BOSELLI C. Sex after stroke: a CNS only dysfunction?[J]. Pharmacol Res, 2006, 54(1): 11-18.
49	STANTON A M, LORENZ T A, PULVERMAN C S, et al. Heart rate variability: a risk factor for female sexual dysfunction[J]. Appl Psychophysiol Biofeedback, 2015, 40(3): 229-237.
50	CLEMENTE-MORAGÓN A, OLIVER E, CALLE D, et al. Neutrophil β1 adrenoceptor blockade blunts stroke-associated neuroinflammation[J]. Br J Pharmacol, 2023, 180(4): 459-478.
51	WANG H, DENG Q W, PENG A N, et al. β-arrestin2 functions as a key regulator in the sympathetic-triggered immunodepression after stroke[J]. J Neuroinflammation, 2018, 15(1): 102.
52	SYKORA M, SIARNIK P, DIEDLER J, et al. β-blockers, pneumonia, and outcome after ischemic stroke: evidence from virtual international stroke trials archive[J]. Stroke, 2015, 46(5): 1269-1274.
53	WANG R H, KÖHRMANN M, KOLLMAR R, et al. Cardiovascular medication seems to promote recovery of autonomic dysfunction after stroke[J]. J Neurol, 2022, 269(10): 5454-5465.
54	LI Y, XIANG W P, ZHANG J F, et al. Are β blockers effective in preventing stroke-associated infections? A systematic review and meta-analysis[J]. Aging (Albany NY), 2022, 14(10): 4459-4470.
55	HAN Z Y, SHEN F X, HE Y, et al. Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress[J]. PLoS One, 2014, 9(8): e105711.
56	WANG Y Y, LIN S Y, CHANG C Y, et al. α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke[J]. Metab Brain Dis, 2023, 38(4): 1249-1259.
57	JIANG Y, LI L L, LIU B, et al. Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat[J]. PLoS One, 2014, 9(7): e102342.
58	LIU Y L, WANG S R, MA J X, et al. Vagus nerve stimulation is a potential treatment for ischemic stroke[J]. Neural Regen Res, 2023, 18(4): 825-831.
59	DAWSON J, LIU C Y, FRANCISCO G E, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial[J]. Lancet, 2021, 397(10284): 1545-1553.
60	LI J N, ZHANG Q B, LI S, et al. α7nAchR mediates transcutaneous auricular vagus nerve stimulation-induced neuroprotection in a rat model of ischemic stroke by enhancing axonal plasticity[J]. Neurosci Lett, 2020, 730: 135031.
61	LONG L, ZANG Q W, JIA G W, et al. Transcutaneous auricular vagus nerve stimulation promotes white matter repair and improves dysphagia symptoms in cerebral ischemia model rats[J]. Front Behav Neurosci, 2022, 16: 811419.

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