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Objectives The purpose of this study was to detect cardiovascular changes after mild severe acute respiratory syndrome coronavirus 2 infection. Background Concern exists that mild coronavirus disease 2019 may cause myocardial and vascular disease. Methods Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post-infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative control subjects were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated cardiovascular magnetic resonance and blood biomarkers). Analysis was blinded, using objective artificial intelligence analytics where available. Results A total of 149 subjects (mean age 37 years, range 18 to 63 years, 58% women) were recruited. Seropositive infections had been mild with case definition, noncase definition, and asymptomatic disease in 45 (61%), 18 (24%), and 11 (15%), respectively, with 1 person hospitalized (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T1, T2, extracellular volume fraction mapping, late gadolinium enhancement) or biomarkers (troponin, N-terminal pro–B-type natriuretic peptide). With abnormal defined by the 75 seronegatives (2 SDs from mean, e.g., ejection fraction 1,072 ms, septal T2 >52.4 ms), individuals had abnormalities including reduced ejection fraction (n = 2, minimum 50%), T1 elevation (n = 6), T2 elevation (n = 9), late gadolinium enhancement (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all N-terminal pro–B-type natriuretic peptide normal). These were distributed equally between seropositive and seronegative individuals. Conclusions Cardiovascular abnormalities are no more common in seropositive versus seronegative otherwise healthy, workforce representative individuals 6 months post–mild severe acute respiratory syndrome coronavirus 2 infection., Central Illustration

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection - some have proposed that Long Covid may be a consequence of either an excessive or inadequate initial response. We analysed SARS-CoV-2 humoral and cellular immunity in healthcare workers infected during the first wave. Symptom questionnaires allowed stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observed no difference in antibody responses to spike, RBD or nucleoprotein, virus neutralisation, or T cell responses. Also, there was no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again showed similar SARS-CoV-2 immunity. Thus, quantitative differences in SARS-CoV-2 adaptive immunity during acute infection are unlikely to contribute to Long Covid causality.

The Omicron, or Pango lineage B.1.1.529, variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection against severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple BioNTech BNT162b2 messenger RNA-vaccinated health care workers (HCWs) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple-vaccinated individuals, but the magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCWs who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.

BACKGROUND COVID-19 data have been generated across the UK as a by-product of clinical care and public health provision, and numerous bespoke and repurposed research endeavours. Analysis of these data has underpinned the UK’s response to the pandemic and informed public health policies and clinical guidelines. However, these data are held by different organisations and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find, navigate permissions to access and interrogate the data they need to inform the pandemic response at pace. OBJECTIVE To transform UK COVID-19 diagnostic datasets to be Findable, Accessible, Interoperable and Reusable (FAIR). METHODS A federated infrastructure model was rapidly built to enable the automated and reproducible mapping of health Data Partners’ pseudonymised data to the OMOP common data model without the need for any data to leave the data controllers’ secure environments and to support federated cohort discovery queries and meta-analysis. RESULTS 56 datasets from 19 organisations are being connected to the federated network. The data includes research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal healthcare records and demographics. The infrastructure is live, supporting aggregate level querying of data across the UK. CONCLUSIONS CO-CONNECT was developed by a multidisciplinary team enabling rapid COVID-19 data discovery, instantaneous meta-analysis across data sources, and is researching streamlined data extraction for egress into a Trusted Research Environment (TRE) for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions whilst maintaining patient confidentiality and local governance procedures. CLINICALTRIAL

Objectives The purpose of this study was to explore the prognostic significance of PTT and PBVi using an automated, inline method of estimation using CMR. Background Pulmonary transit time (PTT) and pulmonary blood volume index (PBVi) (the product of PTT and cardiac index), are quantitative biomarkers of cardiopulmonary status. The development of cardiovascular magnetic resonance (CMR) quantitative perfusion mapping permits their automated derivation, facilitating clinical adoption. Methods In this retrospective 2-center study of patients referred for clinical myocardial perfusion assessment using CMR, analysis of right and left ventricular cavity arterial input function curves from first pass perfusion was performed automatically (incorporating artificial intelligence techniques), allowing estimation of PTT and subsequent derivation of PBVi. Association with major adverse cardiovascular events (MACE) and all-cause mortality were evaluated using Cox proportional hazard models, after adjusting for comorbidities and CMR parameters. Results A total of 985 patients (67% men, median age 62 years [interquartile range (IQR): 52 to 71 years]) were included, with median left ventricular ejection fraction (LVEF) of 62% (IQR: 54% to 69%). PTT increased with age, male sex, atrial fibrillation, and left atrial area, and reduced with LVEF, heart rate, diabetes, and hypertension (model r2 = 0.57). Over a median follow-up period of 28.6 months (IQR: 22.6 to 35.7 months), MACE occurred in 61 (6.2%) patients. After adjusting for prognostic factors, both PTT and PBVi independently predicted MACE, but not all-cause mortality. There was no association between cardiac index and MACE. For every 1 × SD (2.39-s) increase in PTT, the adjusted hazard ratio for MACE was 1.43 (95% confidence interval [CI]: 1.10 to 1.85; p = 0.007). The adjusted hazard ratio for 1 × SD (118 ml/m2) increase in PBVi was 1.42 (95% CI: 1.13 to 1.78; p = 0.002). Conclusions Pulmonary transit time (and its derived parameter pulmonary blood volume index), measured automatically without user interaction as part of CMR perfusion mapping, independently predicted adverse cardiovascular outcomes. These biomarkers may offer additional insights into cardiopulmonary function beyond conventional predictors including ejection fraction., Central Illustration

Background: Electrocardiographic imaging (ECGI) non-invasively maps the heart’s electrical activity through multiple leads on the body surface. Cardiologists need a safe, quick, affordable and re-usable ECGI method to apply to patients undergoing cardiovascular magnetic resonance (CMR), but current solutions are not suitable for high-throughput use. We developed a CMR-ECGI vest for high-throughput use and report the first in vivo results. Methods: We designed and fabricated the CMR-ECGI vest from cotton, containing 256 square (2x2cm) dry textile electrodes each tagged with a localisation marker ( Fig 1 ). Body surface potentials were recorded and co-registered with heart-torso geometries obtained from CMR ( Fig 2 ). Epicardial unipolar potentials were reconstructed using state-of-the-art ECGI algorithms (YR Lab) and local activation and repolarization times were computed using standard methods. Results: Ten healthy volunteers with normal resting ECGs were recruited (34±10years; 60% male). A recumbent 5-minute ECGI recording was performed (preparation time ~15 minutes for montage and doffing). 3 Tesla CMR provided baseline parameters (left ventricular ejection fraction [LVEF] 75±5%, right ventricular [RV] EF 57±5%, native T1 1275±23ms, T2 42±1ms) and showed no clinically significant late gadolinium enhancement. ECGI showed that the sites of earliest and latest activation were the basal RV ( Fig 3A ) and basal-lateral LV respectively ( Fig 3B ). Total duration of epicardial activation and repolarization was 73.3±8.9ms and 195±35.2ms, respectively. These epicardial activation patterns in health are in line with previously described ECGI data. Conclusions: We have developed a re-usable and high-throughput CMR-ECGI solution that is safe and well-tolerated in vivo . This technology is now available for large-scale clinical research use to provide deeper insights into the pathophysiology of arrhythmogenesis, through seamless integration with CMR.

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype‐positive, left ventricular hypertrophy‐negative). Methods and Results A single center, case‐control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre‐phenotypic features of HCM. Individuals with genotype‐positive, left ventricular hypertrophy‐negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH‐fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype‐positive, left ventricular hypertrophy‐negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m 2 , P =0.03), lower left ventricular end‐systolic volume (21.0±6.9 versus 26.7±6.2 mm/m 2 , P ≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤ 0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P =0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls ( P =0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P =0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P =P =0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P =0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

ObjectiveThe coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype.MethodsWe compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage.ResultsCompared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179).ConclusionsThe AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial.

Individuals with likely exposure to the highly infectious SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–5. We hypothesised that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-26–12, would expand in vivo to mediate rapid viral control, potentially aborting infection. We studied T cells against the replication transcription complex (RTC) of SARS-CoV-2 since this is transcribed first in the viral life cycle13–15and should be highly conserved. We measured SARS-CoV-2-reactive T cells in a cohort of intensively monitored healthcare workers (HCW) who remained repeatedly negative by PCR, antibody binding, and neutralisation for SARS-CoV-2 (exposed seronegative, ES). 16-weeks post-recruitment, ES had memory T cells that were stronger and more multispecific than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). The postulate that HCW with the strongest RTC-specific T cells had an abortive infection was supported by a low-level increase in IFI27 transcript, a robust early innate signature of SARS-CoV-2 infection16. We showed that the RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and was preferentially targeted by T cells from UK and Singapore pre-pandemic cohorts and from ES. RTC epitope-specific T cells capable of cross-recognising HCoV variants were identified in ES. Longitudinal samples from ES and an additional validation cohort, showed pre-existing RNA-polymerase-specific T cells expanded in vivo following SARS-CoV-2 exposure, becoming enriched in the memory response of those with abortive compared to overt infection. In summary, we provide evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells, highlighting these highly conserved proteins as targets for future vaccines against endemic and emerging Coronaviridae.

Summary Background We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. Methods We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity. Findings We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27–47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91–0·99), sensitivity 0·84 (0·70–0·93), and specificity 0·95 (0·85–0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91–0·95). Interpretation Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge. Funding Barts Charity, Wellcome Trust, and National Institute of Health Research.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Barts Charity UCLH Charity OnBehalf COVIDsortium Background Recent CMR studies have reported cardiac abnormalities after COVID-19 are common, even after mild, non-hospitalised illness with evidence of ongoing myocardial inflammation. Such a prevalence of chronic myocarditis after mild disease has prompted societal concerns in diverse domains, and suggests that screening should be considered post COVID-19, even in asymptomatic individuals. Cardiovascular magnetic resonance (CMR) has proven utility for diagnosis in patients with COVID-19 infection and elevated troponin from unclear causes by measuring cardiac structure, function, myocardial scar (late gadolinium enhancement) and oedema (T1 and T2 mapping). Objectives We aimed to determine the prevalence and extent of late cardiac and cardiovascular sequelae after mild non-hospitalised SARS-CoV-2 infection. Methods Participants were recruited from COVIDsortium, a three-hospital prospective study of 731 healthcare workers who underwent first wave weekly symptom, PCR and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post infection, 74 seropositive and 75 age-, sex-, ethnicity-matched seronegative controls were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated Cardiovascular Magnetic Resonance and blood biomarkers). Analysis was blinded, using objective AI analytics where available. Results 149 subjects (mean age 37 years, range 18-63, 58% female) were recruited. Seropositive infections had been mild with case definition/non-case definition/asymptomatic disease in 45(61%), 18(24%) and 11(15%) with one person hospitalised (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass; atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterisation (T1, T2, ECV mapping, late gadolinium enhancement) or biomarkers (troponin, NT-proBNP). With abnormal defined by the 75 seronegatives (2 standard deviations from mean, e.g. EF 1072ms, septal T2 > 52.4ms), individuals had abnormalities including reduced EF (n = 2, minimum 50%), T1 elevation (n = 6), T2 elevation (n = 9), LGE (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all NT-proBNP normal). These were distributed equally between seropositive and seronegative individuals. Conclusions Cardiovascular abnormalities are no more common in seropositive vs seronegative otherwise healthy, workforce representative individuals 6 months post mild SARS-CoV-2 infection. Our study provides societal reassurance for the cardiovascular health of working-aged individuals with convalescence from mild SARS-CoV-2. Screening asymptomatic individuals following mild diseases is not indicated.

Aims Microvascular dysfunction in hypertrophic cardiomyopathy (HCM) is predictive of clinical decline, however underlying mechanisms remain unclear. Cardiac diffusion tensor imaging (cDTI) allows in vivo characterization of myocardial microstructure by quantifying mean diffusivity (MD), fractional anisotropy (FA) of diffusion, and secondary eigenvector angle (E2A). In this cardiac magnetic resonance (CMR) study, we examine associations between perfusion and cDTI parameters to understand the sequence of pathophysiology and the interrelation between vascular function and underlying microstructure. Methods and results Twenty HCM patients underwent 3.0T CMR which included: spin-echo cDTI, adenosine stress and rest perfusion mapping, cine-imaging, and late gadolinium enhancement (LGE). Ten controls underwent cDTI. Myocardial perfusion reserve (MPR), MD, FA, E2A, and wall thickness were calculated per segment and further divided into subendocardial (inner 50%) and subepicardial (outer 50%) regions. Segments with wall thickness ≤11 mm, MPR ≥2.2, and no visual LGE were classified as ‘normal’. Compared to controls, ‘normal’ HCM segments had increased MD (1.61 ± 0.09 vs. 1.46 ± 0.07 × 10−3 mm2/s, P = 0.02), increased E2A (60 ± 9° vs. 38 ± 12°, P Conclusion In HCM patients, even in segments with normal wall thickness, normal perfusion, and no scar, diffusion is more isotropic than in controls, suggesting the presence of underlying cardiomyocyte disarray. Increased E2A suggests the myocardial sheetlets adopt hypercontracted angulation in systole. Increased MD, most notably in the subendocardium, is suggestive of regional remodelling which may explain the reduced subendocardial blood flow.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Clinical Research Training Fellowship Background Pulmonary transit time (PTT) is a quantitative biomarker of cardiopulmonary status. Rest PTT was previously shown to predict outcomes in specific disease models, but clinical adoption is hindered but challenges in data acquisition. Whether evaluation of PTT during stress encodes incremental prognostic information has not been previously investigated as scale. Objectives To compare the prognostic value of stress and rest PTT derived from a fully automated, in-line method of estimation using perfusion CMR, in a large patient cohort. Methods A retrospective two-center study of patients referred clinically for adenosine stress myocardial perfusion assessment using CMR. Analysis of right and left ventricular cavity arterial input function curves from first pass perfusion was performed automatically, allowing the in-line estimation of both rest and stress PTT. Association with major adverse cardiovascular events (MACE) was evaluated. MACE was defined as a composite outcome of myocardial infarction, stroke, heart failure admission and ventricular tachycardia or appropriate ICD treatment (including ICD shock and/or anti-tachycardia pacing). Results 985 patients (67% male, median age 62 years (IQR 52,71)) were included, with median left ventricular ejection fraction (LVEF) of 62% (IQR 54-69). Median stress PTT was shorter than rest PTT 6.2 (IQR 5.1, 7.7) seconds versus 7.7 (IQR, 6.4, 9.2) seconds. Stress and rest PTT were highly correlated (r = 0.69; p Conclusions In this 2-center study of 985 patients, we deploy a fully automated method of PTT estimation using perfusion mapping with CMR and show that both stress and rest PTT are independently associated with adverse cardiovascular outcomes. In this patient cohort, there is no clear incremental prognostic value of stress PTT, over its evaluation during rest. Figure 1. Stress and Rest Pulmonary Transit Time estimation using myocardial perfusion CMR Figure 2. Event-free survival curves for major adverse cardiovascular events (Heart failure hospitalization, myocardial infarction, stroke and ventricular tachycardia/ICD treatment) according to mean rest PTT (8.05seconds) and mean stress PTT (6.7seconds). Log-rank for both p

Background Takotsubo cardiomyopathy (TTS) is an extremely rare complication of fluorouracil containing chemotherapy regimes such as FOLFOX used for colorectal cancer, occurring in only five previous case reports. Due to its potentially fatal outcomes, yet infrequent presence in the literature, it is worthwhile reviewing the clinical features and outcomes of this phenomenon. Case summary A 54-year-old lady was admitted with cardiogenic shock. A cardiac magnetic resonance imaging (CMR) showed mid-ventricle to apical hypokinesis and confirmed TTS. She was managed with inotropes and non-invasive ventilation after which she recovered fully both clinically and in her CMR features 6 weeks following discharge. Discussion This is the first case showing the acute CMR features of this complication and highlights the need for awareness of this rarely occurring cardiotoxicity. It also shows the potentially fatal phenomenon can be fully reversible when diagnosed and managed promptly even in patients with metastatic cancer and critical illness.

We hypothesised that host-response biomarkers of viral infections may contribute to early identification of SARS-CoV-2 infected individuals, critical to breaking chains of transmission. We identified 20 candidate blood transcriptomic signatures of viral infection by systematic review and evaluated their ability to detect SARS-CoV-2 infection, compared to the gold-standard of virus PCR tests, among a prospective cohort of 400 hospital staff subjected to weekly testing when fit to attend work. The transcriptional signatures had limited overlap, but were mostly co-correlated as components of type 1 interferon responses. We reconstructed each signature score in blood RNA sequencing data from 41 individuals over sequential weeks spanning a first positive SARS-CoV-2 PCR, and after 6-month convalescence. A single blood transcript for IFI27 provided the highest accuracy for discriminating individuals at the time of their first positive viral PCR result from uninfected controls, with area under the receiver operating characteristic curve (AUROC) of 0.95 (95% confidence interval 0.91–0.99), sensitivity 0.84 (0.7–0.93) and specificity 0.95 (0.85–0.98) at a predefined test threshold. The test performed equally well in individuals with and without symptoms, correlated with viral load, and identified incident infections one week before the first positive viral PCR with sensitivity 0.4 (0.17–0.69) and specificity 0.95 (0.85–0.98). Our findings strongly support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection, for screening individuals such as contacts of index cases, in order to facilitate early case isolation and early antiviral treatments as they emerge.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Quantitative myocardial perfusion mapping using Cardiac Magnetic Resonance (CMR) imaging is used for evaluation of ischaemia in the context of native vessel coronary disease, but its diagnostic performance in patients with grafts is not well established. Perfusion defects are often detected in these patients, but whether these are a consequence of a technical limitation (delayed contrast arrival from graft conduits) or a true reflection of reduced myocardial blood flow is unclear. Methods 39 patients undergoing stress perfusion CMR with previous coronary artery bypass graft (CABG) surgery, unobstructed left internal mammary artery (LIMA) grafts to the left anterior descending (LAD) artery on coronary angiography and no CMR evidence of prior LAD infarction were included. Myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) were evaluated with quantitative perfusion mapping and the factors determining MBF in the LIMA-LAD territory (AHA segments 1,2,7,8,13,14), including the impact of delayed contrast arrival through the LIMA graft were evaluated. Results In 28 out of 39 cases a myocardial perfusion defect was reported on visual assessment in LIMA-LAD myocardial territory, despite the presence of unobstructed LIMA graft and no LAD infarction. Chronic total occlusion (CTO) of the native LAD was an independent predictor of stress MBF (B=-0.36, p =0.027) and the strongest predictor of MPR (B=-0.55, p 0.005) within the LIMA-LAD myocardial territory after adjusting for age, left ventricular (LV) ejection fraction, and presence of diabetes. CTO of the native LAD was associated with a reduction in stress MBF in the basal myocardial segments (-0.57ml/g/min, p = 0.002) but had no effect on the MBF of apical segments (-0.31ml/g/min, p = 0.084). Increasing the maximum value for allowable arterial delay (TA) of contrast in the quantitative mapping algorithm resulted in a small increase in myocardial blood flow in the LIMA-LAD territory both at stress (0.07 ± 0.08ml/g/min, p Conclusions Perfusion defects detected in LIMA-LAD subtended territories are common despite graft patency. These defects are likely to represent genuine reduction in MBF, resulting from native LAD coronary occlusion. Prolonged contrast transit time associated with LIMA grafts results in small underestimation of MBF as measured by quantitative CMR perfusion mapping, but does not account for the degree of MBF reduction seen in these patients. Figure 1. Study patient with unobstructed LIMA to LAD graft and evidence of inducible perfusion defect in LIMA-LAD territories. (A): First pass perfusion CMR imaging. (B): Perfusion mapping showing reduced stress MBF in mid antero-septum (0.85ml/g/min) compared to the apical septum (1.65ml/g/min). (C): Late gadolinium enhancement showing no evidence of previous infarction. (D,E): Coronary angiography demonstrating unobstructed LIMA graft (D) and anastomosis site (E). Abstract Figure 1.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by a Clinical Training Research Fellowship (K. Knott) from the British Heart Foundation and directly and indirectly from the Biomedical Research Centre at University College London Hospitals and Barts Heart Centre. Background Cardiovascular magnetic resonance (CMR) with automated inline perfusion mapping permits rapid fully automated non-invasive myocardial blood flow (MBF, ml/g/min). Understanding the microvascular component of MBF would help optimize epicardial coronary artery disease detection and potentially serve as an independent diagnostic / therapeutic target. Purpose To explore MBF influences at stress and rest in patients with unobstructed epicardial coronary arteries. Methods 242 participants (mean age 56.9 years) from 5 European centers with unobstructed epicardial coronary arteries and no myocardial scar underwent adenosine vasodilator perfusion mapping at stress and rest. The factors influencing MBF were determined using univariate and multivariate linear regression analyses. Results Mean rest perfusion was 0.91+/-0.24ml/g/min. Rest perfusion was higher in females (0.97+/-0.22ml/g/min vs 0.83 +/- 0.24ml/g/min) and lower in patients on beta blockers. Mean stress MBF was 2.53+/-0.82ml/g/min. Factors independently associated with reduced stress MBF were increasing age, diabetes, increasing left ventricular mass (LVMi) and the use of beta blockers. The predicted stress MBF can be obtained from the equation MBF = 2.66–0.015(age-60)–0.013(LVMi-57)-0.405(diabetes)–0.365(beta blocker). This means stress MBF falls 10% over 19 years and that diabetes drops the MBF by the equivalent of being 27 years older. These changes are large: for example, a 70-year-old diabetic would have 30% lower stress MBF than a 35 year-old non-diabetic. Conclusions In the absence of obstructive epicardial coronary disease, stress MBF falls with age, diabetes, increased LV mass and beta-blockers. These data may help develop normal reference ranges, input to other modelling (eg CT FFR), and they advance perfusion mapping as a measure of microvascular function. Abstract Figure. Summary of the determinants of perfusion

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Guy"s and St Thomas" Charity University College London Hospital Biomedical Research Centre Background In people with obesity, bariatric surgery reduces mortality, heart failure and coronary disease, improving metabolic (blood sugar, lipid profile, inflammation) and cardiovascular (diastolic/systolic function, filling pressure, cardiac remodelling) parameters. Myocardial microvascular function is a candidate causal link of metabolic to structural cardiac abnormalities. Purpose We hypothesised that bariatric surgery could improve myocardial microvascular and mechanical function in both those with and without diabetes. Methods Before and six months after bariatric surgery, 24 subjects with obesity were assessed with haematology, biochemistry and advanced CMR (cines, vasodilator adenosine stress and rest fully-automated quantitative perfusion mapping, tissue-tracking (CVI42, post processing). Results. Mean age was 49± 12 years, 35%(8) were male, 63%(15), had hypertension, 17 (71%) had diabetes. Surgery resulted in decreases in BMI (44 ± 7 to 34 ± 6 kg/m2 p = 0.0001) and HbA1c (57 ± 16 to 42 ± 9mmol/mol p = 0.0001). EF% and absolute LV end-diastolic volumes remained unchanged, but mass regressed and myocardial contraction fraction (ratio of stroke volume and LV volume) increased (see Table). There were also strain improvements (radial 35 ± 8.8 to 37.3 ± 8.7 %p = 0.029) (circumferential -19.8 ± 2.3 vs -20.7 ± 3% p = 0.017), although longitudinal did not improve (-16.3 ± 3.2 to -15.9 ± 3% p = 0.25). Myocardial perfusion significantly improved (stress myocardial blood flow, MBF 2.35 ± 0.71 to 2.80 ± 0.98 ml/g/min p = 0.008; myocardial perfusion reserve MPR 2.47 ± 0.78 to 2.97 ± 0.95 p = 0.005). Improvement in stress MBF and MPR from pre-operative to post-operative was higher in the non-diabetics (n = 7 (29%)) than the diabetics (n = 17 (71%)) (stress MBF: 1.15 ± 1.00 vs 0.16 ± 0.39ml/g/min p = 0.002) MPR: (1.09 ± 0.73 vs 0.25 ± 0.66 p = 0.011). Conclusion At 6 months, bariatric surgery results in beneficial myocardial remodelling and substantial improvements in myocardial microvascular function. These improvements occur most in those without diabetes suggesting that there may be reversible and irreversible components to microvascular dysfunction. Perfusion and strain variables Variable Pre-op (n = 24) Post-op (n = 24) p-value LVEDV (ml) 163 ± 28 161 ± 29 0.64 EF (%) 70 ± 8 70 ± 7 0.78 Stroke volume (ml) 113 ± 19 111 ± 21 0.6 LV Mass (g) 117 ± 25 103 ± 21 0.001 Myocardial contraction fraction 94 ± 14 105 ± 14 0.001 LVEDV - left ventricular end-diastolic volume, EF - ejection fraction Abstract Figure.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Guy"s and St Thomas" Charity University College London Hospitals Biomedical Research Centre Background Obesity and cardiovascular disease are associated, but the relationship is poorly understood. Myocardial perfusion, metabolic derangement and lipotoxicity appear adversely associated in many scenarios (myocardial injury, diastolic dysfunction, diabetes). Altered perfusion (by PET) predicts outcome, and it is hypothesised that perfusion derangement is part of causality for cardiac disease and adverse outcomes. Purpose To assess the presence and pattern of myocardial microvascular dysfunction in patients with obesity (scheduled for bariatric surgery) using stress quantitative perfusion mapping. Methods 38 subjects with obesity planned to undergo bariatric surgery and 38 age and sex matched healthy volunteers (no diabetes, no hypertension) underwent anthropometry, biochemistry and CMR at 1.5T (Siemens) with cine imaging, stress (adenosine 140-210 mcg/kg/min) and rest fully-automated quantitative perfusion mapping. Results Bariatric patients had a higher BMI (44 ± 6.4 vs 26.5 ± 4kg/m2 p = 0.001); 58%(22) were diabetic and 58%(22) had hypertension. Bariatric patients had higher absolute but lower indexed end-diastolic volumes, and overall higher ejection fractions (+5%) (see Table). Rest myocardial blood flow (MBF) in bariatric patients was the same (1.00 ± 0.3 vs 0.88 ± 0.24 p = 0.052), but stress perfusion results were significantly lower both for stress MBF (2.35 ± 0.69 vs 2.93 ± 0.76ml/g/min p = 0.001) and myocardial perfusion reserve (MPR 2.48 ± 0.82 vs 3.4 ± 0.81ml/g/min p = 0.0001). Although this was transmural, the endocardial stress MBF was particularly negatively affected in the bariatric cohort compared to controls (endocardial MBF 2.16 ± 0.65 vs 2.82 ± 0.73ml/g/min, p = 0.0001 vs epicardial MBF: 2.52 ± 0.76 vs 3.06 ± 0.79 p = 0.003), meaning there was an increased endo-epicardial stress MBF gradient in bariatric patients (0.87 ± 0.12 vs 0.92 ± 0.07 p = 0.03). Conclusion Compared to healthy controls, patients with obesity have abnormal myocardial stress perfusion with reduced global perfusion, perfusion reserve and an increased transmyocardial perfusion gradient. Table - myocardial perfusion parameters Category Bariatric patients n = 38 Controls n = 38 p value Age (years) 48 ± 11 45 ± 13 0.25 n male (%) 12 (32%) 10 (36%) 0.32 LVEDV (ml) 168 ± 37 149 ± 31 0.017 LVEDVi (ml/m2) 70.4 ± 12.3 78.8 ± 12.1 0.004 LV Mass (g) 116 ± 31 99 ± 28 0.019 EF (%) 70 ± 8 65 ± 5 0.002 LVEDV - left ventricular end-diastolic volume, EF - ejection fraction

Background Extrinsic coronary compression is an extremely rare complication of aortic root abscess formation and can manifest as an acute coronary syndrome in infective endocarditis. Optimal management strategies are unknown and therefore illustrative case reports may be informative. Case summary We describe a 63-year-old man with a background history of a mechanical aortic valve who developed sepsis due to Escherichia coli bacteraemia from a presumed urinary source. He suddenly deteriorated with cardiogenic shock and anterior ST-segment elevation myocardial infarction on Day 16 and received emergency percutaneous coronary intervention for severe stenoses of left anterior descending and diagonal arteries. A transoesophageal echocardiogram 2 days later demonstrated a large aortic root abscess. He was transferred for emergency surgery which revealed a large aortic abscess surrounding the left main stem confirming extrinsic coronary compression. He received a redo tissue aortic valve replacement and repair of his abscess cavity. Discussion We describe a case where percutaneous coronary intervention and emergency surgery was used to treat extrinsic compression from an aortic root abscess; a complication that is associated with a high mortality. This is also a rare case of E. coli causing prosthetic valve endocarditis. We also explore the findings of 11 previous cases of extrinsic coronary compression from aortic root abscess.

BACKGROUND: SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. METHODS: Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. FINDINGS: A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p