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Principal Investigator: Meher R Juttukonda
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2021
Award: $462,000
Funding agency: National Institute on Aging
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE Inhibitors><ACE2><Affect><Amentia><AngII><Angiotensin AT1 Receptor><Angiotensin AT2 Receptor><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II><Angiotensin II Receptor><Angiotensin II Type 1 Receptor><Angiotensin Receptor><Angiotensin Receptor 2><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensins><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Apoplexy><Arteriosclerotic Dementia><Autoregulation><BOLD response><BP control><BP homeostasis><BP management><BP regulation><Binding><Blood><Blood Pressure><Blood Reticuloendothelial System><Blood Vessels><Brain><Brain Nervous System><Brain Vascular Accident><Brain Vascular Disorders><Brain imaging><CO2><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><CV19><Carbon Dioxide><Carbonic Anhydride><Caring><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrovascular Stroke><Cerebrovascular system><Cessation of life><Clinical Trials><CoV-2><CoV2><Communities><Consumption><Contracting Opportunities><Contracts><Control Groups><Coupled><Death><Dementia><Deterioration><Diabetes Mellitus><Disease><Disorder><Drugs><Dysfunction><Electroencephalogram><Electrophysiology><Electrophysiology (science)><Encephalon><Energy Supply><Ensure><Enzyme Antagonist><Enzyme Gene><Enzyme Inhibitor><Enzyme Inhibitor Agent><Enzyme Inhibitor Drugs><Enzymes><Equilibrium><Functional disorder><Future><Goals><Health Care Systems><Healthcare Systems><Homeostasis><Hormone Receptor><Human><Hypertension><Hypotensive Agent><Hypotensive Drugs><Hypotensives><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Individual><Infection><Intracellular Communication and Signaling><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Ischemic Stroke><Kininase II Antagonists><Kininase II Inhibitors><Lead><Lisinopril><Losartan><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Medicine><Methods><Modeling><Modern Man><Molecular Interaction><NMR Imaging><NMR Tomography><Neurophysiology / Electrophysiology><Nuclear Magnetic Resonance Imaging><Outcome><Participant><Pathway interactions><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacological Treatment><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Prevention><Prinivil><Procedures><Production><Receptor, Angiotensin, Type 1><Receptor, Angiotensin, Type 2><Regulation><Renin-Angiotensin System><Research><Research Proposals><Rest><Risk><Risk Factors><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Spin Labels><Stimulus><Stroke><Survivors><System><Testing><Time><Type 2 Angiotensin II Receptor><Vascular Dementia><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Wuhan coronavirus><Zestril><Zeugmatography><acute care><age dependent><age related><angiotensin converting enzyme 2><angiotensin converting enzyme II><assault><balance><balance function><biological signal transduction><blood oxygen level dependent><blood oxygenation level dependent><blood oxygenation level dependent response><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><brain attack><brain blood flow><brain blood vessels><brain tissue><brain vascular disease><brain vascular dysfunction><brain vasculature><brain visualization><cerebral blood flow><cerebral blood vessel><cerebral circulation><cerebral vascular><cerebral vascular accident><cerebral vascular disease><cerebral vascular dysfunction><cerebral vasculature><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular accident><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovascular vessels><cerebrovasculature><clinical care><compare effectiveness><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cost><design><designing><diabetes><drug/agent><electrophysiological><fMRI/EEG><flexibility><flexible><functional magnetic resonance imaging/electroencephalography><hCoV19><heavy metal Pb><heavy metal lead><high blood pressure><high risk><hyperpiesia><hyperpiesis><hypertension control><hypertension management><hypertension treatment><hypertensive disease><image-based method><imaging><imaging method><imaging modality><imaging study><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><intracranial vascular dysfunction><lozartan><math analysis><math methodology><math methods><mathematical analysis><mathematical approach><mathematical methodology><mathematical methods><mathematics analysis><mathematics approach><mathematics methodology><mathematics methods><nCoV2><neural><neural network><neuro-vascular coupling><neurovascular coupling><novel><pandemic><pandemic disease><pathogen><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><preservation><prevent><preventing><regulate BP><regulate blood pressure><relating to nervous system><respiratory><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><vascular><vascular contributions to dementia>