key: cord-1042361-qmck9pp9 authors: Mangion, Kenneth; Morrow, Andrew; Bagot, Catherine; Bayes, Hannah; Blyth, Kevin G; Church, Colin; Corcoran, David; Delles, Christian; Gillespie, Lynsey; Grieve, Douglas; Ho, Antonia; Kean, Sharon; Lang, Ninian N; Lennie, Vera; Lowe, David; Kellman, Peter; Macfarlane, Peter W; McConnachie, Alex; Roditi, Giles; Sykes, Robert; Touyz, Rhian M; Sattar, Naveed; Wereski, Ryan; Wright, Sylvia; Berry, Colin title: The Chief Scientist Office Cardiovascular and Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study date: 2020-07-23 journal: Cardiovasc Res DOI: 10.1093/cvr/cvaa209 sha: cb3dc27cfacc53285012daf7e8bd7bf2dd28df0b doc_id: 1042361 cord_uid: qmck9pp9 BACKGROUND: COVID-19 is typically a primary respiratory illness with multisystem involvement. The prevalence and clinical significance of cardiovascular and multisystem involvement in COVID-19 remain unclear. METHODS: This is a prospective, observational, multicentre, longitudinal, cohort study with minimal selection criteria and a near-consecutive approach to screening. Patients who have received hospital care for COVID-19 will be enrolled within 28 days of discharge. Myocardial injury will be diagnosed according to the peak troponin I in relation to the upper reference limit (URL, 99th centile) (Abbott Architect troponin I assay; sex-specific URL, male: >34 ng/L; female: >16 ng/L). Multisystem, multimodality imaging will be undertaken during the convalescent phase at 28 days post-discharge (Visit 2). Imaging of the heart, lung, and kidneys will include multiparametric, stress perfusion, cardiovascular magnetic resonance imaging, and computed tomography coronary angiography. Health and well-being will be assessed in the longer term. The primary outcome is the proportion of patients with a diagnosis of myocardial inflammation. CONCLUSION: CISCO-19 will provide detailed insights into cardiovascular and multisystem involvement of COVID-19. Our study will inform the rationale and design of novel therapeutic and management strategies for affected patients. Background COVID-19 presents the most significant threat to human health in modern times [1] [2] [3] [4] . The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes COVID-19 illness, is mediated by tropism for nasopharyngeal and pulmonary epithelial cells. Cardiovascular complications are common, affecting around 1 in 4 patients, associate with prior cardiovascular disease, and increase the risk of death [5] [6] [7] [8] [9] [10] . Cardiovascular injury may be secondary to inflammation, hypoxia, hypotension, and thrombosis or, potentially, through virus invasion of endothelial cells, vascular smooth muscle cells and pericytes leading to vascular injury or dysfunction. This mechanism may then play a primary role in the development of pathology 11 . The angiotensin converting enzyme 2 (ACE2) transmembrane receptor, which normally has protective effects in the cardiovascular system, is also the receptor which mediates virus transmission in human cells, including in the cardiovascular system 12, 13 . Coronavirus (Coronaviridae family) is named after the crown morphology of its outer membrane. SARS-CoV-1, which caused an epidemic in 2002-2003, and SARS-CoV-2, infect human cells when the surface spike (S)-protein, a type 1 membrane glycoprotein 10, 12 binds to the ACE2 transmembrane receptor protein on human cells. SARS-CoV-1 and SARS-CoV-2 have 76% similarity in their S proteins. Fusion of the coronavirus S-protein with the cell surface ACE2 transmembrane receptor internalises the virus promulgating replication and dissemination. ACE2 is expressed in endothelial cells in the heart, lungs, kidneys, intestine and testis [14] [15] [16] and is a member of the counter-regulatory axis of the renin angiotensin aldosterone system (RAAS) 17 . In its canonical function, as a carboxypeptidase, ACE2 is protective in the cardiovascular system through its role in metabolising Ang I to Ang- (1) (2) (3) (4) (5) (6) (7) (8) (9) and Ang II to Ang- (1) (2) (3) (4) (5) (6) (7) , therefore reducing Ang II levels and generating the protective peptides Ang-(1-9) and Ang-(1-7) which act through the angiotensin type 2 receptor 18, 19 and Mas receptor 20 , respectively. Like SARS-CoV-2, SARS-CoV-1 virus also uses ACE2 and transmembrane protease serine 2 (TMPRSS2) as mechanisms of cell invasion. During SARS-CoV-1 infection of transgenic mice expressing human ACE2, ACE2 becomes dysregulated and depleted 21 . In acute lung disease triggered by sepsis, ACE2 is directly protective 22 . SARS patients may experience overwhelming immune and inflammatory responses, in the form of a cytokine storm, leading to left ventricular (LV) systolic dysfunction, arrhythmias and sudden death 23, 24 . Imaging is therefore well placed to investigate the underlying pathology of myocardial injury in COVID- 19 patients. Chan et al 25 provided preliminary evidence of coronavirus infection in pulmonary endothelial cells. Varga et al studied histopathology of heart, lung, kidney and liver tissue samples from 3 patients who died from COVID-19. They found evidence of viral elements within endothelial cells and endotheliitis 11 . Recent studies suggest that systemic manifestions of COVID-19, including hypertension, thrombosis, myocardial involvement and kidney failure, may be due to endothelial and vascular disease 26 High levels of ACE2 are expressed by pericytes in the heart 16 and cardiomyocytes (7.5%, scRNA-seq data) 27 . ACE2 may have paradoxical roles since ordinarily it regulates a vasculoprotective signalling pathway and has protective catalytic effects in the lung. On the other hand, it is a receptor for virus transmission into human cells. SARS-CoV-2 infection reduces the activity and/or protein levels of ACE2 leading to a harmful imbalance of AngII/AT1R effects 28 . ACE2 overexpression enhances the stability of atherosclerotic plaque 29 . However, ACE2 transcript and protein levels are increased in patients with cardiovascular disease e.g. heart failure 16 , and post-MI 30 , implying an increased risk of cardiac infection. The association between COVID-19 and RAAS inhibitor therapy 31, 32 and other cardiovascular medications 21 is most likely explained by underlying cardiovascular disease 31 . There have been a number of case reports or case series of reported COVID-19 associated myocardial injury, presenting as myocarditis 2, 5, 33, 34 or reverse takotsubo 35, 36 . A number of autopsy reports identify SARS-CoV-2 RNA in the myocardium of patients dying from COVID-19 related complications (pulmonary embolism and pneumonitis 37 , undefined 38 ) whilst other series do not identify myocardial SARS-CoV-2 RNA in the context of death related to pneumonitis and acute respiratory distress syndrome (ARDS) [39] [40] [41] [42] . Taken together, this suggests that there are several potential mechanisms of myocardial injury (endotypes) in severe SARS-CoV-2 infection and that further research is warranted. Endothelial damage and thrombotic microvascular angiopathy may underpin systemic vascular dysfunction 10 . Autopsy studies have shown evidence of this at a pulmonary microvascular level and this may be responsible in part for the severe hypoxia present in these patients 43 . The prevalence of renal involvement in patients with SARS-CoV-2 infection is low 44, 45 , and is hypothesised to be secondary to cytokine damage, systemic effects of the illness 44 or interaction between the cardio-pulmonary axis and renal function, as has been reported in ARDS 46 . Acute myocardial injury is defined as a rise in the circulating concentration of troponin above the 99th percentile of the upper reference limit and then a fall. Acute MI is myocardial injury in the context of myocardial ischaemia. Acute MI is categorised into one of 5 types 47 . Type 1 MI is diagnosed based the occurrence of at least one of the following: 1) Symptoms of acute myocardial ischaemia; 2) New ischaemic ECG changes; 3) Development of pathological Q waves; 4) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology; 5) Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy. Clinical scenarios of Type 1 MI include coronary plaque rupture and plaque erosion. A diagnosis of Type 2 MI is based on evidence of an imbalance between myocardial oxygen supply and demand unrelated to coronary thrombosis, requiring at least one of the following: 1) Symptoms of acute myocardial ischaemia; 2) New ischaemic ECG changes; 3) Development of pathological Q waves; 4) Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology. Clinical scenarios of Type 2 MI include severe hypertension, hypoxia and tachyarrhythmia. Type 3 MI is the classification used for patients who suffer cardiac death due to MI and Types 4 and 5 MI are iatrogenic, consequent on MI arising from PCI or CABG, respectively 47 . The diagnosis of myocardial infarction with no obstructive coronary arteries (MINOCA) indicates that there is an ischaemic mechanism responsible for the myocyte injury. Clinical scenarios for MINOCA include MI due to atherosclerotic plaque rupture i.e. type 1 MI, coronary spasm, spontaneous coronary dissection and Type 2 MI. Myocardial injury is diagnosed based on elevated cardiac biomarkers without myocardial ischaemia. Acute myocardial injury is associated with a rise and fall of troponin whereas chronic myocardial injury is associated with a stable troponin concentration. Myocardial injury may be primarily due to a cardiac or non-cardiac cause 48 . Cardiac causes of myocardial injury include arrhythmias and disorders of coronary vascular function. Non-cardiac causes include of myocardial injury include anaemia and pulmonary embolism 48 . The plasma concentration of troponin I will be measured using the Abbott Architect assay. The sex-specific upper reference limits (99 th centile) are >16 ng/L and >34 ng/L for females and males, respectively. Cardiovascular MRI (CMR) is a non-invasive diagnostic test for myocardial pathology [49] [50] [51] . Through tissue characterisation, CMR can differentiate between myocardial inflammation (acute vs. chronic), myocardial infarction (acute vs. chronic scar), and pericarditis, and simultaneously provide information on cardiac function, blood flow and incidental findings e.g. pericardial effusion 49, 50, 52, 53 . In COVID-19, myocardial inflammation due to viral myocarditis, ischaemia, or stress cardiomyopathy, as well as MINOCA (Type 1 or Type 2 MI) and other cardiac complications are potentially more common than previously thought based on current crude biomarker studies. Establishing their real frequency using powerful imaging techniques is essential for optimising risk stratification and optimal therapy. In our study, MRI will be used to assess for and classify clinical endotypes. The endotypes of myocardial involvement are 1) myocardial inflammation e.g. 1.1) myocarditis, 1.2) ischaemia, or 1.3) stress (Takotsubo) cardiomyopathy, 2) myocardial infarction, 3) indeterminate, or 4) none. A diagnosis of viral myocarditis typically requires endomyocardial biopsy (EMB). We do not anticipate EMB will be undertaken in our study population, therefore, a presumptive diagnosis may be made based on the available clinical information. The wide field of view of the chest and abdomen also permits imaging of the lungs and kidneys. A CT coronary angiogram/chest protocol will image for coronary artery disease, delayed enhancement, lung perfusion, PTE and parenchymal pathology. Taken together, integration of multimodality imaging of the heart, lungs and kidneys within a single visit represents a highly novel approach to investigate the cardiovascular complications of COVID-19. The imaging scans will also support advanced computational modelling to better understand this multisystem disease. We hypothesize that myocarditis (myocardial inflammation) is common after SARS-CoV-2 infection. 7. To establish sub-studies using computational cardiovascular modelling, electrocardiography and pathology. The CISCO-19 study has a prospective, observational, multicentre, longitudinal, cohort design, minimal selection criteria and a near-consecutive approach to screening. The study population will be focused on COVID-19 patients who have survived the initial, acute illness. Accordingly, the findings from our study are most relevant to patients in the convalescent phase looking forward to the longer term. We will characterize cardiac involvement evidenced by an increase in circulating high sensitivity troponin I > upper reference limit at any time during the hospital episode of care. Control data may be drawn from local cohorts, as appropriate. Patients who received hospital care with COVID-19 will be enrolled within 28 days of discharge. This enrolment strategy is intended to maximize enrolment of all-comers affected by COVID-19. Patients who die or are ineligible for other reasons will be recorded in a screening log. Multi-parametric, stress perfusion, cardiovascular MRI, computed tomography coronary angiography (CTCA) and a 12-lead ECG will be acquired at approximately 28 days postdischarge. The study is designed to assess for imaging evidence of multiorgan injury ( Figure 2 ). The study will involve multiple centres in the West of Scotland (population 2.2 million) including the Queen Elizabeth University Hospital, the Royal Infirmary in Glasgow, and the Royal Alexandra Hospital in Paisley. These hospitals provide secondary care services for NHS Greater Glasgow and Clyde Health Board ( Figure 3 ). Patients with a diagnosis of COVID-19 will be identified from clinical databases. The clinical pathways include but are not limited to: (1) Emergency Medicine and in-patient wards; and (2) laboratory records. The inclusion criteria are: (1) age >18 years old; (2) history of hospital attendance or hospitalisation for COVID-19, confirmed by a clinical diagnosis, laboratory test e.g. PCR and/or a radiological test e.g. CT chest or chest X-ray; (3) able to comply with study procedures; (4) able to provide written informed consent. The radiology results will be reported by accredited radiologists according to contemporary, national guidelines. The exclusion criteria are: (1) contra-indication to CMR e.g. severe claustrophobia, metallic foreign body; (2) contra-indication to intravenous adenosine, i.e. severe asthma; long QT syndrome; second-or third-degree AV block and sick sinus syndrome; and (3) lack of informed consent. We aim to screen a near-consecutive cohort of patients diagnosed with COVID-19. A screening log will be prospectively completed. The reasons for being ineligible, including lack of inclusion criteria and/or presence of exclusion criteria, will be prospectively recorded. This information will characterise selection bias, if any. One hundred and eighty patients will be enrolled following written informed consent. If a consented patient is subsequently found to be ineligible, unless consent is withdrawn, they will remain included in the study population, including consent for long term follow up using linkage of electronic government and patient records (EPR). A diagnosis of COVID-19 will be based either laboratory evidence of SARS-CoV-2 infection using a PCR test on a biospecimen or a radiological diagnosis consistent with COVID-19 but biospecimen negative 54 . The laboratory tests used are either the Roche Cobas 6800 or Seegene SARS-CoV-2 tests. The current protocol involves two visits. The first visit involves informed consent and baseline assessments. The second visit occurs at 28 days after discharge. A third visit is intended at one year, contingent on additional funding and a protocol amendment being secured. A proposed vascular biology sub-study involves a gluteal skin biopsy after 28 days. The participants will be invited to consent for life-long follow-up using electronic record linkage without direct contact. The study assessments involve gathering information from standard of care procedures and research tests (Appendix). The standard of care information include demographics, medical history (including multimorbidity), limited examination, laboratory and radiological tests, cardiology tests (including an ECG and an echocardiogram if clinically indicated) and treatment. The research assessments at both visits include blood and urine samples, a 12-lead digital ECG (Beneheart R3, Mindray), health status questionnaires and assessments of adverse events. Visit 2 involves cardiovascular imaging, including stress perfusion MRI and CTCA and an ECG. By designating imaging during the convalescent phase, at 28 days post-discharge, the participants are not anticipated to be infectious. This approach aligns with other contemporary studies, such as the International Severe Acute Respiratory and Emerging Infection Coronavirus Clinical Characterisation Consortium-4 (ISARIC-4C) study 55 . Since MRI and CTCA are appropriately not performed during the acute phase, some pathologies that might have been detected acutely may have resolved by 28 days. Therefore, all clinical information obtained during Visits 1 and 2 will be used to inform the diagnosis of myocardial injury. Prior cardiovascular disease includes diabetes, hypertension, myocardial infarction, heart failure, stroke, and transient ischemic attack. Cardiovascular risk factors include age, cigarette smoking, obesity, hypertension, hyperlipidaemia, and glycated haemoglobin. Cardiovascular risk will be described using established using the established JBS3 and Heart Age Scores. The primary outcome for our study is a diagnosis of myocarditis (myocardial inflammation). The relevant endotypes are 1) myocardial inflammation due to 1.1) myocarditis, 1. Myocardial inflammation is caused by the immune response to virus infection, autoimmune disease, ischemic injury, or toxic agents 49 . MRI provides a noninvasive approach to characterizing acute and chronic myocardial pathology. Expert consensus recommendations for the CMR-based diagnosis of definite myocardial inflammation include one T2-based criterion (global or regional increase of myocardial T2 relaxation time or an increased signal intensity in T2-weighted CMR images), with at least one T1-based criterion (increased myocardial T1, extracellular volume, or late gadolinium enhancement) 49, 50 . Having just one criterion may support a diagnosis of probable myocardial inflammation. A key attribute of the imaging protocol in our study involves the prioritized assessment of myocardial perfusion using pharmacological stress testing with intravenous adenosine. This approach is intended to permit classification of myocardial injury as being ischemic or non-ischemic, to facilitate classification of myocardial infarction versus ischemic or non-ischemic myocardial inflammation. Information on myocardial perfusion will provide insights into coronary microvascular dysfunction that may, potentially, occur following COVID-19 51 . Information from CTCA will clarify the presence or absence of obstructive CAD and MINOCA. A panel of 3 or more cardiologists will assess the clinical information to make a diagnosis (endotype) and related certainty (Not/unlikely = no; Probable/Very = Yes) before and after disclosure of the MRI and CTCA findings. The diagnosis will be based on consensus. This approach reflects the uncertainty in determining a diagnosis in patients with myocardial injury. The diagnosis draws upon clinical information and test results, rather than any single test modality in isolation. A prioritised secondary outcome is the endotype for myocardial injury, including myocardial infarction type according to the 4 th Universal Definition of MI 47 , and myocarditis (myocardial inflammation, ischaemia or stress cardiomyopathy) 49, 50 . We aim to assess the impact of cardiovascular complications on health status, well-being and physical function. We will prospectively collect patient reported outcome measures (PROMS) in order to assess for associations with the cardiovascular complications of COVID-19, reflected by the primary and secondary outcomes. Self-reported health status will be assessed using the generic EuroQOL EQ-5D-5L questionnaire and the Brief Illness Perception Questionnaire (Brief-IPQ) 56, 57 . We will utilize the Patient Health Questionnaire-4 (PHQ-4) to assess for anxiety and depressive disorders 58 . Participants will be invited to complete these questionnaires at each visit. The Duke Activity Status Index (DASI) provides a measure of functional capacity and a higher score reflects greater physical function 59 Physical Activity Questionnaire -Short Form (IPAQ-SF) measures the types of intensity of physical activity and sitting time that people do as part of their daily lives. The score reflects total physical activity in MET-min/week and time spent sitting 60 . In order to research the mechanisms of cardio-pulmonary and renal involvement of SARS-CoV-2 infection, we will measure circulating biomarkers of inflammation (CRP, ferritin, IL-6), cardiac injury (troponin I, NTproBNP), renin angiotensin system (aldosterone, sACE2,) and haemostasis (coagulation screen, Clauss Fibrinogen, DDimer, FVIII (one stage), VWF Antigen and VWF:GP1ba, antithrombin, protein C, and free protein S)), and renal function (albumin:creatinine ratio) and their changes over time. The measurements will be undertaken in a central laboratory, blind to the other clinical data. The associations between the circulating concentrations of these mechanistic biomarkers, including their changes over time, and the primary and secondary outcomes will be assessed. Cardiovascular MRI is the reference diagnostic method for myocardial injury, including myocarditis and acute cardiomyopathy. Stress perfusion MRI using intravenous adenosine enables dynamic imaging of myocardial blood flow during stress and rest conditions. In-line pixel mapping enables fully quantitative read-out of myocardial blood flow (ml/min/g tissue), classified at a sub-segmental level (32-myocardial segments) with the % extent of myocardium with impaired perfusion during stress (% ischemic burden) [61] [62] [63] [64] [65] [66] . All of this information can be spatially mapped with LV function, tissue characteristics revealed by T2-mapping, native Tmapping, late gadolinium enhancement (LGE) and extracellular volume (ECV) 52 . In this study, the modified Lake Louise criteria will be used to diagnose definite myocardial inflammation (T2 map + T1 (native T1, LGE or ECV abnormal)) or probable myocardial inflammation (either T2 or T1 abnormal) 49, 50 . In order to limit selection bias, renal dysfunction is not an exclusion criterion. Patients with severe renal dysfunction (GFR <30 ml/kg/m 2 ) will be considered for contrast MRI according to local Radiology protocols. SARS-CoV-2 causes vascular dysfunction and microthrombotic angiopathy 10 MRI will also provide information for incidental findings in the chest e.g. pulmonary arterial thrombus, and abdomen. Imaging renal anatomy, size and tissue characterization will be exploratory. The CT scanner has 320-detectors enabling full heart coverage within a single heartbeat (Aquilion ONE, Canon). Intravenous metoprolol will be used where required to control the heart rate (target 60/min) and sublingual glyceryl trinitrate will be given to all patients immediately before the scan acquisition. An initial low radiation dose helical scan of the thorax will be acquired for comprehensive assessment of the lungs. A contrast bolus timing scan will be acquired which will provide information on cardiopulmonary transit times. Non-contrast and contrast-enhanced angiographic breath-hold ECG-gated volumes will be acquired timed for optimum pulmonary and systemic arterial (coronary) opacification. CTCA will provide information on the presence and extent of coronary calcification (calcium score), coronary artery disease, and whether CAD is obstructive (flow-limiting) including the CAD-RADS score. Intracardiac thrombus will be assessed. Late enhancement ECG-gated CT will be acquired for to assess for delayed enhancement (scar) 67 and ECV calculation 68 . Pulmonary vascular imaging will assess pulmonary vascular thrombosis (embolism) including CT obstruction score, cardiopulmonary transit times and measures of raised PA & right heart pressures (PA, caval and azygous dimensions plus hepatic IVC reflux). CT will also characterise pulmonary features associated with COVID infection (percentage ground glass opacity, percentage consolidation & CO-RADS score) plus pre-existing lung damage (percentage emphysema). CT will also assess for signs of osteoporosis and sarcopenia as frailty markers. The CT and MRI findings will be correlated with the other clinical data. Cardiac and extracardiac findings will be reported and managed according to local standards of care. Patients with severe renal dysfunction thought to be at risk of acute kidney injury as determined by local Radiology clinical protocols will undergo non-contrast CT. In order to assess the natural history, longer-term follow-up for health outcomes will be undertaken using electronic record linkage omitting the need for participants to undergo further research visits after the 12-month visit. The scans will be pseudoanonymised i.e. identifiers removed and assigned a unique study number to enable linkage. The scans will be shared with research collaborators for cardiovascular modelling to better understand the relationships between tissue pathology, blood flow and function. COVID-19 infection and treatment is associated with changes on the ECG. The changes include alterations in heart rate, conduction and ventricular repolarisation. Drug treatment for COVID-19 may prolong the QTc interval. Whether these changes persist after the acute phase and their relations with myocardial pathology are unknown. Paper and/or digital ECGs will be acquired, de-identified and provided to the University of Glasgow Electrocardiography Core Laboratory for automated analysis. The ECG measures will be linked with the clinical and imaging data. We will undertake exploratory research into the vascular biology of COVID-19 infection. This work will be undertaken in collaboration with cardiovascular scientists and virologists in the University of Glasgow. We will study the vascular biology of cells and molecules e.g. RNA and cytokines, implicated in SARS-CoV-2. Informed consent will be obtained for post mortem examination in the event of death during the study period. Histology samples of the heart will be examined for features of myocarditis, myocardial infarction and microvascular disease. The histopathological findings will be linked to the CMR findings. This study has been developed with input from members of a multidisciplinary research team and the Scientific Strategy Group of the University of Glasgow. The study has been peer reviewed by panel members of the Chief Scientist Office of the Scottish Government. The study has been reviewed by the Patient and Public Involvement group of NHS Greater Glasgow and Clyde Health Board. The statistical analyses will be pre-defined according to a Statistical Analysis Plan. The primary outcome is myocarditis (myocardial inflammation). To detect an association between a history of pre-existing cardiovascular disease and the incidence of myocardial inflammation (myocarditis) at 2-4 weeks we have assumed 25% of patients with prior cardiovascular disease and the incidence of myocardial inflammation in those with/without prior cardiac problems to be 33% and 10%, respectively. To have 80% power to detect this difference will require 140 participants (35 with cardiac problems, 105 without) to be scanned. We aim for 160 patients to attend the imaging visit, anticipating that 10-15% of the participants may have incomplete imaging data due to technical reasons e.g. imaging artefact or claustrophobia. Pre-specified subgroup analyses are intended for patients without cardiovascular disease, as defined by the absence of (1) prior cardiovascular disease and (2) obstructive coronary artery disease on CTCA. Given the public health significance of COVID-19, interim reports may be undertaken. Outcome assessments (endpoint adjudication) will be undertaken in blinded fashion. The primary outcome evaluation (myocardial injury endotype) will be adjudicated by a panel of cardiologists blind to the clinical status of the patient and performed according to a prespecified charter. The trial will be conducted in line with the current Guidelines for Good Clinical Practice in Clinical Trials and STROBE guidelines 69 . The Study Management Group (SMG) includes those individuals responsible for the day-to-day management of the study including the chief investigator, project manager and representatives from the sponsor. The role of this group will be to facilitate the progress of the study, ensure that the protocol is adhered to and take appropriate action to safeguard participants and the quality of the study itself. Decisions about continuation or termination of the study or substantial amendments to the protocol will be the responsibility of the sponsor. A scientific steering group will oversee the study. This study is designed to be undertaken and reported rapidly in response to the global need for information about COVID-19. The CISCO-19 study is approved by the UK National Research Ethics Service (Reference 20/NS/0066). CISCO-19 is an investigator-initiated clinical study that is funded by the Chief Scientist Office of the Scottish Government (MR/S018905/1). The funder has no role in the study design, conduct (non-voting TSC member), data analysis and interpretation, manuscript writing, or dissemination of the results. The MRI study involves imaging and analyses technologies provided by Siemens Healthcare and the National Institutes of Health The trial is co-sponsored by NHS Greater Glasgow & Clyde and the University of Glasgow. The ClinicalTrials.gov identifier is NCT04403607. Our observational, multimodality, imaging cohort study will prospectively gather information on the cardiovascular complications and their clinical significance in COVID-19. A relatively unselected approach to patient enrolment will minimise selection bias outwith those who do not survive or who are unable to comply with the protocol. The findings will be generalizable to patients in the convalescent phase of the illness and informative for the natural history. On the other hand, the findings will not necessarily be generalizable to all patients with COVID-19, since our enrolment strategy focuses on survivors following the acute phase of the illness. Cardiovascular MRI will be used to clarify clinical endotypes according to contemporary guidelines 49, 50 . Quantitative measurements of myocardial blood flow at stress and rest will enable focused research into coronary microvascular dysfunction that may be secondary to endotheliitis caused by SARS-CoV-2. CT imaging will clarify the presence and relevance of coronary artery disease and MINOCA, lung pathology and pulmonary arterial thrombosis. Renal MRI will be undertaken on an exploratory basis to assess kidney size (differential volume) plus both global values and cortico:medullary ratios for T1, T2 and apparent diffusion coefficient (ADC) for correlation with renal function. Renal dysfunction is not an exclusion criterion, reflecting the open approach to enrolment. Taken together with a comprehensive clinical assessment, laboratory tests (including renal function and urine albumin:creatine ratio), and circulating biomarkers, our study will characterize multi-system involvement of SARS- High sensitivity troponin is a cardiac protein that is ubiquitously released from injured cardiomyocytes. However, troponin is not cause-specific and circulating concentrations may increase due to hypoxia, hypotension, and renal failure as well from direct cardiac toxicity. It is unclear whether cardiovascular involvement in COVID-19 is mainly secondary to severe pneumonia, or whether there is direct viral infection of the heart and blood vessels. A recent expert consensus guideline highlighted the pivotal diagnostic value of cardiac MRI in the diagnosis of myocardial inflammation due to viruses, autoimmune disease, ischemic injury and toxic agents. MRI is diagnostically useful to identify endotypes for stratified therapy. We will assess whether this could be the case in COVID-19. To our knowledge, CISCO-19 is the first to apply stress perfusion cardiac MRI to assess and quantify abnormalities in myocardial perfusion that may be secondary to microvascular dysfunction. The information on myocardial perfusion will help classify patients with myocardial injury into ischemic or non-ischemic groups. Stress perfusion MRI is not usually undertaken in patients with myocarditis, and quantitative measurements of myocardial blood flow are a key attribute to our study design. We aim to advance new knowledge into the pathogenesis of myocardial inflammation (ischemic vs. non-ischemic) and into the associations between the etiology of disease with abnormalities in myocardial perfusion. Recent advances in fully quantitative, in-line pixel-mapping of myocardial perfusion are uniquely enabling to quantify myocardial blood flow in near real-time without the need for time-intensive, off-line post-processing. In addition, multimodality imaging involves multi-parametric cardiovascular MRI and CTCA during the same visit. As such, our study will provide methodologically robust estimates of persisting myocardial injury and the impact on the physical and mental wellbeing of the participants. The results should be helpful to inform clinical management strategies for the diagnosis and management of patients recovering from COVID-19. Our study will provide complementary information to add to the growing body of knowledge on multisystem involvement in COVID-19. We will collect information on participants' characteristics at baseline including demographics, anthropometry, cardiovascular and medical history, and health status. The participants will be invited to give informed consent for life-long follow-up by linkage of electronic patient records. Using multivariable analyses we will link the patients' characteristics at baseline to observations during longer term follow-up in order to characterize the natural history of this condition. Our imaging research will clarify the prevalence and clinical significance of cardiopulmonary injury (notably myocardial inflammation) in patients with COVID-19, which is a major knowledge gap in the NHS. By adopting an all-comers approach we will identify patients with myocardial inflammation that is sub-clinical (i.e. not diagnosed) or clinically overt. By correlating the MRI findings with troponin and other measures of cardiovascular injury, such as BNP, our results will potentially inform NHS care pathways to use these blood tests in a more directed manner for the clinical management of patients with COVID-19. Currently, there are no disease-modifying therapies for myocarditis, including due to SARS-CoV-2. Overall, our study will add new knowledge on the natural history of COVID-19 in a comparatively unselected population. Our study will create a unique biorepository of clinical samples and images, which in turn, may be exploited by scientists undertaking mechanistic research into the vascular biology of SARS-CoV-2 infection, and cardiovascular modelling. Sarah Allwood-Spiers PhD, George Bruce BSc, Rosario Gonzalez-Lopez PhD, Pauline Hall Barrientos PhD, Aleksandra Radjenovic PhD, Rebecca Stace BSc. Contributors: CB designed the study and wrote the first draft of the manuscript with KM. The coauthors reviewed the manuscript drafts. Each author has individually contributed to either the delivery of the study or helped to devise aspects of the study protocol. All authors have given final approval for the current version to be published. 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We would thank the CISCO-19 Study  Circulating biomarkers of inflammation (