肾素-血管紧张素系统(RAS)调节剂,包括血管紧张素受体阻滞剂(ARB)和血管紧张素转换酶抑制剂(ACEI),是控制血压的有效药物。认知缺陷,包括注意力不集中,记忆丧失,和混乱,在COVID-19感染后报告。ARBs或ACEI增加血管紧张素转换酶-2(ACE-2)的表达,一种允许SARS-CoV-2刺突蛋白结合用于细胞入侵的功能性受体。迄今为止,RAS调节剂的使用与COVID-19认知功能障碍严重程度之间的关联仍存在争议.
目的:这项研究解决了以下问题:1)RAS调节剂的先前治疗是否会使COVID-19引起的脑血管和认知功能障碍恶化?2)RAS调节剂的后处理能否改善COVID-19后的认知表现和脑血管功能?我们假设治疗前加剧了COVID-19引起的有害作用,而治疗后显示出保护作用。
方法:临床研究:通过电子病历系统识别2020年5月至2022年12月被诊断为COVID-19的患者。纳入标准包括用至少一种抗高血压药物治疗的高血压病史。随后,患者分为两组:入院前接受过ACEI或ARB处方的患者和入院前未接受过此类治疗的患者.入院时评估每位患者的神经功能障碍迹象。临床前研究:人源化ACE-2转基因敲入小鼠通过颈静脉注射接受SARS-CoV-2刺突蛋白2周。一组接受了氯沙坦(10mg/kg),ARB,注射前两周在他们的饮用水中,而另一组在注射刺突蛋白后开始氯沙坦治疗。认知功能,脑血流量,测定所有实验组的脑血管密度。此外,评估血管炎症和细胞死亡.
结果:在入院前服用ACEI/ARBs的177例患者中,有97例(51%)出现了神经功能障碍的迹象。118例患者中有32例(27%)未接受ACEI或ARB。在动物研究中,刺突蛋白注射增加血管炎症,内皮细胞凋亡增加,脑血管密度降低。并行,刺突蛋白降低脑血流量和认知功能。我们的结果表明,氯沙坦预处理会加剧这些影响。然而,氯沙坦治疗后可预防刺突蛋白诱导的血管和神经功能障碍。
结论:我们的临床数据表明,在遇到COVID-19之前使用RAS调节剂最初会加剧血管和神经功能障碍。在体内实验中证明了类似的发现;然而,当在刺突蛋白注射后开始治疗时,靶向RAS的保护作用在动物模型中变得明显。
Renin-angiotensin system (RAS) modulators, including Angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI), are effective medications for controlling blood pressure. Cognitive deficits, including lack of concentration, memory loss, and confusion, were reported after COVID-19 infection. ARBs or ACEI increase the expression of angiotensin-converting enzyme-2 (ACE-2), a functional receptor that allows binding of SARS-CoV-2 spike protein for cellular invasion. To date, the association between the use of RAS modulators and the severity of COVID-19 cognitive dysfunction is still controversial.
OBJECTIVE: This study addressed the following questions: 1) Does prior treatment with RAS modulator worsen COVID-19-induced cerebrovascular and cognitive dysfunction? 2) Can post-treatment with RAS modulator improve cognitive performance and cerebrovascular function following COVID-19? We hypothesize that pre-treatment exacerbates COVID-19-induced detrimental effects while post-treatment displays protective effects.
METHODS: Clinical study: Patients diagnosed with COVID-19 between May 2020 and December 2022 were identified through the electronic medical record system. Inclusion criteria comprised a documented medical history of hypertension treated with at least one antihypertensive medication. Subsequently, patients were categorized into two groups: those who had been prescribed ACEIs or ARBs before admission and those who had not received such treatment before admission. Each patient was evaluated on admission for signs of neurologic dysfunction. Pre-clinical study: Humanized ACE-2 transgenic knock-in mice received the SARS-CoV-2 spike protein via jugular vein injection for 2 weeks. One group had received Losartan (10 mg/kg), an ARB, in their drinking water for two weeks before the injection, while the other group began Losartan treatment after the spike protein injection. Cognitive functions, cerebral blood flow, and cerebrovascular density were determined in all experimental groups. Moreover, vascular inflammation and cell death were assessed.
RESULTS: Signs of neurological dysfunction were observed in 97 out of 177 patients (51%) taking ACEIs/ARBs prior to admission, compared to 32 out of 118 patients (27%) not receiving ACEI or ARBs. In animal studies, spike protein injection increased vascular inflammation, increased endothelial cell apoptosis, and reduced cerebrovascular density. In parallel, spike protein decreased cerebral blood flow and cognitive function. Our results showed that pretreatment with Losartan exacerbated these effects. However, post-treatment with Losartan prevented spike protein-induced vascular and neurological dysfunctions.
CONCLUSIONS: Our clinical data showed that the use of RAS modulators before encountering COVID-19 can initially exacerbate vascular and neurological dysfunctions. Similar findings were demonstrated in the in-vivo experiments; however, the protective effects of targeting the RAS become apparent in the animal model when the treatment is initiated after spike protein injection.