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

感染 COVID-19 的高血压患者脑血管治疗中 RAS 抑制剂类别的比较

• 批准号: 10196006
• 负责人: Meher R Juttukonda
• 金额: $ 46.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196006
• 关键词: 2019-nCoV; ACE2; Affect; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Binding; Blood; Blood Pressure; Blood Vessels; Brain; Brain imaging; COVID-19; COVID-19 patient; Carbon Dioxide; Caring; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cessation of life; Clinical Trials; Communities; Consumption; Contracts; Control Groups; Coupled; Dementia; Deterioration; Diabetes Mellitus; Disease; Electroencephalogram; Electrophysiology (science); Energy Supply; Ensure; Enzyme Inhibitor Drugs; Enzymes; Equilibrium; Functional disorder; Future; Goals; Healthcare Systems; Homeostasis; Hormone Receptor; Human; Hypertension; Image; Imaging Techniques; Individual; Infection; Ischemic Stroke; Lead; Lisinopril; Losartan; Magnetic Resonance Imaging; Measurement; Measures; Medicine; Methods; Modeling; Outcome; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Prevention; Procedures; Production; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Research; Research Proposals; Rest; Risk; Risk Factors; SARS-CoV-2 infection; Sampling; Shapes; Signal Transduction; Spin Labels; Stimulus; Stroke; Survivors; System; Testing; Time; Type 2 Angiotensin II Receptor; Vascular Dementia; acute care; age related; assault; blood oxygen level dependent; blood oxygenation level dependent response; blood pressure regulation; brain tissue; cerebrovascular; clinical care; compare effectiveness; cost; design; flexibility; functional magnetic resonance imaging/electroencephalography; high risk; hypertension control; hypertension treatment; imaging modality; imaging study; inhibitor/antagonist; innovation; mathematical analysis; mathematical methods; neural network; neurovascular coupling; novel; pandemic disease; pathogen; preservation; prevent; relating to nervous system; respiratory; response

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.

抽象的。越来越明显的是，许多人的脑血管系统正受到攻击 感染了 COVID-19。最近的研究发现，高血压患者患高血压的风险增加两倍 死于 COVID-19 感染，并且 100% 的感染患者接受了磁共振成像 (MRI) 检查显示 CBF 减少，其中 23% 显示有缺血性中风的证据。这 COVID-19 导致的脑血管失调可能会加重中风和本已巨大的负担 与年龄相关的血管恶化有关的痴呆症。引起 COVID-19 的病原体 SARS-CoV-2 现在已知，疾病会降低一种称为 ACE2 的酶的功能，ACE2 是肾素的主要调节因子。 控制血压和脑血流量（CBF）的血管紧张素系统（RAS）。这种 SARS-CoV-2 病理生理学可能导致 1 型血管紧张素受体 (AT1R) 过度刺激，但减少 刺激 2 型血管紧张素受体 (AT2R)，这可能会加剧高血压并扰乱 CBF 自动调节和神经血管耦合。幸运的是，目前可用的抗高血压药物有两类 药物旨在通过抑制 AT1R 来调节 RAS。然而，可能存在关键差异 在这两个类之间。血管紧张素 II 受体阻滞剂 (ARB) 可以保护 CBF 前体的活性 AT2R，因此可能比其他类别更有效地预防脑血管失调， 称为 ACE (ACEIs) 的酶抑制剂，可抑制 AT2R 活性。 该 R21 研究提案的目标是比较 ARB 和 ACEI 降压药的有效性 预防感染新冠病毒的高血压患者出现长期脑血管失调的药物 19. 我们实验室最近开发的两种新型成像方法将用于评估 CBF 自动调节 严重感染后至少 1 年进行神经血管耦合 (NVC)。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 (BOLD) MRI 结合新颖的方法测量基线 CBF 和自动调节能力 由于时间相关的差异，将血管信号的幅度与污染分开的分析。 其次，我们将同时获取静息态脑电图和 BOLD MRI 来估计身体的 调节血管能量输送以响应神经需求变化的能力 电生理活动。我们将通过尖端数学分析来量化这种 NVC，以检测 EEG 中网络活动的瞬态并模拟时间一致的局部 BOLD MRI 响应。 该方法的成功实施将为 CBF 调节提供灵敏的测量 高血压 COVID-19 幸存者，这表明一类抗高血压药物可能更有效 面对与 COVID-19 相关的失调，CBF 管理有效，这表明临床的紧迫性 在患有 COVID-19 的高血压患者中进行 RAS 抑制剂试验，以优化未来的临床护理。