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; 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。越来越清楚的是，脑血管系统在许多人中受到攻击 在最近的研究中，发现高血压患者的风险增加了两倍 死于Covid-19感染，100％接受磁共振成像的感染患者 （MRI）检查了CBF减少，23％显示了表明缺血性中风的证据。这 由于COVID-19引起的脑血管失调可能会增加中风的巨大烧伤和 与年龄相关的血管确定相关的痴呆症。病原体SARS-COV-2，导致COVID-19 现在已知疾病可以降低称为ACE2的酶的功能，该酶是肾素中的主要调节剂 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过量刺激1型血管紧张素受体（AT1R），但降低 刺激2型血管紧张素受体（AT2R），这可能既加剧高血压又会破坏 CBF自动调节和神经血管耦合。幸运的是，两类目前可用的降压 药物旨在通过抑制AT1R来调节RAS。但是，可能有关键的区别 在这两个类之间。血管紧张素II受体阻滞剂（ARB）受到Pro-CBF活性的保护 AT2R，因此可能更有效地预防脑血管失调，而不是其他类别 称为ACE（ACEI）的酶的抑制剂，该酶抑制AT2R活性。 这项R21研究建议的目的是比较ARB和ACEI降压的有效性 药物预防长期脑血管失调的高血压患者感染了共证 19.最近在我们的实验室中开发的两种新型成像方法将被利用以评估CBF自动调节 严重感染后至少1年，神经血管耦合（NVC）。首先，我们将进行无创 优化的动脉自旋标记（ASL）MRI和呼吸挑战加权血液氧合水平 - 依赖（BOLD）MRI，以测量基线CBF和自动调节能力与新型相结合 由于时间相关的差异而导致的分析使血管信号的幅度与污染的幅度分析。 其次，我们将获得简单的静止状态脑电图和大胆的MRI，以估计身体的 根据中性的需求变化，调节血管能量输送的能力 电生理活性。我们将通过检测到的尖端数学分析来量化这一NVC 脑电图中网络活动的瞬态状态，并建模局部局部粗体MRI响应。 这种方法的成功实施将提供对CBF法规的敏感测量 高血压的共同199生存，并表明一类降压药可能更多 面对COVID-19与19与COVID相关的失调有效，有效 高血压患者COVID-19的RAS抑制剂的试验，以优化未来的临床护理。