Comparison of RAS inhibitor classes for cerebrovascular management in hypertensive patients who contracted COVID-19 infection

抽象的。越来越清楚的是，许多人的脑血管系统受到攻击 感染了新冠病毒在最近的研究中，发现高血压患者患高血压的风险增加了两倍。 死于COVID-19感染，100%的感染患者接受了磁共振成像 (MRI)检查显示CBF降低，23%显示缺血性卒中的证据。的 COVID-19导致的脑血管失调可能会增加中风的巨大负担， 与年龄相关的血管恶化相关的痴呆。引起COVID-19的病原体SARS-CoV-2 疾病，现在已知会降低称为ACE 2的酶的功能，ACE 2是肾素-血管紧张素Ⅱ的主要调节因子， 控制血压和脑血流量（CBF）的血管紧张素系统（RAS）。这个SARS-CoV-2 病理生理学可能导致1型血管紧张素受体（AT 1 R）过度刺激，但降低 刺激2型血管紧张素受体（AT 2 R），这可能会加剧高血压，并破坏 CBF自动调节和神经血管耦合。幸运的是，目前可用的两类抗高血压药物 药物被设计为通过抑制AT 1 R来调节RAS。然而，可能有一个关键的区别， 在这两个阶级之间。血管紧张素II受体阻滞剂（ARB）可保护脑血流量前体对脑组织的活性， AT 2 R，因此可能比其他类别更有效地预防脑血管失调， 一种称为ACE的酶的抑制剂（ACEIs），其抑制AT 2 R活性。 这项R21研究计划的目的是比较ARB和ACEI降压的有效性 预防感染COVID的高血压患者长期脑血管失调的药物- 19.我们实验室最近开发的两种新的成像方法将被用来评估CBF自动调节 和神经血管偶联（NVC）至少在严重感染后1年。首先，我们将进行非侵入性的 优化的动脉自旋标记（ASL）MRI和呼吸挑战加权血氧水平- 依赖性（BOLD）MRI测量基线CBF和自动调节能力， 将血管信号的幅度与由于时序相关差异引起的污染解耦的分析。 其次，我们将同时获得静息态脑电图和BOLD MRI，以估计身体的 调节血管能量输送以响应神经系统需求变化的能力 电生理活动我们将用尖端的数学分析来量化这种NVC， EEG中网络活动的瞬态，并对时间一致的局部BOLD MRI响应进行建模。 这种方法的成功实施将提供CBF监管的敏感测量， 高血压COVID-19幸存者，并表明一类抗高血压药物可能更多 在面对COVID-19相关失调时有效地进行CBF管理，证明了临床 RAS抑制剂在COVID-19高血压患者中的试验，以优化未来的临床护理。

Abstract. It has become increasingly clear that the cerebrovascular system is under assault in many individuals infected with COVID-19. In recent studies, patients with hypertension were found at a two-fold increased risk of dying from COVID-19 infection, and 100% of infected patients who received a magnetic resonance imaging (MRI) exam showed reduced CBF with 23% showing evidence indicative of ischemic stroke. The cerebrovascular dysregulation due to COVID-19 may add to the already enormous burden of stroke and dementia associated with age-related vascular deterioration. The pathogen SARS-CoV-2, causing COVID-19 illness, is now known to reduce function of an enzyme termed ACE2 that is a major regulator in the Renin- Angiotensin system (RAS) that controls blood pressure and cerebral blood flow (CBF). This SARS-CoV-2 pathophysiology might lead to excessive stimulation of type 1 angiotensin receptor (AT1R) but reduced stimulation of type 2 angiotensin receptor (AT2R), which is likely to both exacerbate hypertension and disrupt CBF autoregulation and neurovascular coupling. Fortunately, two classes of currently available antihypertensive medications are designed to regulate RAS by inhibiting AT1R. However, there may be a critical difference between these two classes. Angiotensin II receptor blockers (ARBs) are protective of the pro-CBF activity on the AT2R, and thus may be more effective at preventing the cerebrovascular dysregulation than the other class, inhibitors of an enzyme termed ACE (ACEIs), which inhibit AT2R activity. The goal of this R21 research proposal is to compare the effectiveness of ARB and ACEI antihypertensive medicines in preventing long-term cerebrovascular dysregulation in hypertensive patients infected with COVID- 19. Two novel imaging methods recently developed in our lab will be leveraged to assess CBF autoregulation and neurovascular coupling (NVC) at least 1 year after the severe infection. First, we will conduct noninvasive optimized arterial spin labeling (ASL) MRI and respiratory challenge-weighted blood oxygenation level- dependent (BOLD) MRI to measure baseline CBF and autoregulatory capacity in combination with novel analyses that decouple the magnitude of vascular signal from contamination due to timing-related differences. Second, we will acquire simultaneous resting-state electroencephalogram and BOLD MRI to estimate the body’s capacity to adjust vascular energy delivery in response to changes in the demand from neural electrophysiological activity. We will quantify this NVC with cutting-edge mathematical analysis that detects transient states of network activity in EEG and models the time-concordant local BOLD MRI responses. Successful implementation of this approach would offer sensitive measurement of CBF regulation in hypertensive COVID-19 survivors and would indicate that one class of antihypertensive medication may be more effective in CBF management in the face of COVID-19-related dysregulation, demonstrating urgency of clinical trials of RAS inhibitors in hypertensive patients with COVID-19 to optimize future clinical care.