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。越来越清楚的是，许多人的脑血管系统受到了攻击 感染了新冠肺炎。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。 死于新冠肺炎感染，100%接受磁共振成像的感染患者 核磁共振(MRI)检查显示脑血流量减少，其中23%显示有缺血性中风的证据。这个 新冠肺炎导致的脑血管调节失调可能会增加本已巨大的中风和高血压负担 与年龄相关的血管恶化相关的痴呆症。引起新冠肺炎的病原体SARS-CoV-2 现已知，疾病会降低一种名为ACE2的酶的功能，ACE2是肾素-2的主要调节因子 血管紧张素系统(RAS)，控制血压和脑血流(CBF)。这是SARS-CoV-2 病理生理可能导致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和扰乱 脑血流量自动调节和神经血管偶联。幸运的是，目前可用的两类降压药 药物旨在通过抑制AT1R来调节RAS。然而，可能会有一个关键的区别 在这两个阶层之间。血管紧张素II受体阻滞剂(ARB)可保护 AT2R，因此在预防脑血管紊乱方面可能比另一类更有效， 一种称为血管紧张素转换酶(ACEI)的酶的抑制剂，它抑制AT2R的活性。 R21研究提案的目标是比较ARB和ACEI的降压效果 预防感染柯萨奇病毒的高血压患者长期脑血管调节障碍的药物- 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)在严重感染后至少1年。首先，我们将进行非侵入性 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测量基线脑血流量和自动调节能力 分析将血管信号的大小从污染中分离出来，这是由于与时间相关的差异。 其次，我们将获得同步的静息脑电和大胆的磁共振成像来估计身体的 调节血管能量输送的能力以响应神经需求的变化 电生理活动。我们将使用尖端的数学分析来量化这种NVC EEG中网络活动的瞬时状态，并对时间一致的局部BOLD MRI反应进行建模。 成功实施这一方法将提供对以下方面的CBF监管的敏感衡量 高血压新冠肺炎幸存者并会表明，一类降压药可能会更多 有效应对新冠肺炎相关脑血流失调，彰显临床紧迫性 RAS抑制剂在新冠肺炎高血压患者中的试验以优化未来的临床护理。