Regulatory T (Treg) cells are powerful endogenous modulators of the immune response and their levels are reduced in patients with acute coronary syndromes (ACSs). Low-dose interleukin-2 (IL-2) has been shown to increase Treg cell levels, potentially providing an immunomodulatory strategy in ACSs. The IVORY trial was a double-blind, placebo-controlled, phase 2 trial in which patients presenting with ACSs and high-sensitivity C-reactive protein levels >2 mg l-1 were randomized in a 1:1 ratio to receive subcutaneous low-dose IL-2 (1.5 × 106 IU) or placebo for 8 weeks. [18F]Fluorodeoxyglucose positron emission tomography-computed tomography of the ascending aorta and carotid arteries was performed before and after treatment. Here the primary outcome was the difference in arterial inflammation in the index vessel (the vessel with the highest average maximum target-to-background ratio pre-treatment) on follow-up imaging between the two groups (placebo = 29 (female-to-male ratio (F-to-M) = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)). At the end of treatment, arterial inflammation was -0.171 (-7.7%) lower in the low-dose IL-2 group compared to the placebo group (95% confidence interval -0.308 to -0.034, P = 0.015). In secondary efficacy analyses, the difference in arterial inflammation between the low-dose IL-2 and placebo groups was greater (-8.3%, P = 0.009) in more inflamed segments and low-dose IL-2 treatment increased Treg cell levels compared to placebo (P < 0.0001). Low-dose IL-2 treatment appeared to be safe, with no major adverse cardiovascular events at the 2-year follow-up, compared to three patients with such events in the placebo group. In conclusion, in patients with ACSs, low-dose IL-2 safely increases Treg cell levels and reduces arterial inflammation. The clinical benefit of low-dose IL-2 requires validation in larger studies. ClinicalTrials.gov registration: NCT04241601 .

Systemic vasculitides are complex multisystem immune‐mediated inflammatory diseases, classified by the affected vessel size, which are associated with a wide range of clinical manifestations and complications. The most common forms of large vessel vasculitis (LVV) are giant cell arteritis and Takayasu arteritis, although other more rare causes exist. Cranial giant cell arteritis is the most commonly diagnosed form of LVV, affects older adults and can result in sudden visual loss and stroke. Up to 80% of individuals with giant cell arteritis have LV involvement, which can exist with or without cranial involvement. Takayasu arteritis usually occurs in those under the age of 60 years, resulting in progressive injury of the aorta and its main branches. LVV may also affect the coronary and pulmonary circulations, as well as the pericardium and myocardium resulting in a range of cardiovascular pathologies. Diagnosing LVV can be challenging in the absence of a disease‐specific laboratory biomarker, and relies on a combination of inflammatory markers, imaging, and temporal artery biopsy when required. Noninvasive multimodality imaging techniques are advancing and provide new avenues for diagnosis and disease monitoring. High‐resolution ultrasound, magnetic resonance imaging, and computed tomography can survey the pattern and extent of arterial involvement and reveal signs of active inflammation. Positron emission tomography imaging with 18 F‐fluorodeoxyglucose and novel radiotracers provide more sensitive measures of vascular inflammation of the large vessels. Ultimately, these imaging tests can be used to guide therapeutic interventions and inform the clinical use of new targeted disease modifying therapies for LVV.

Aims While acute cardiovascular complications of coronavirus disease 2019 (COVID-19) are well described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19.Methods and results Twenty-one participants {mean age 47 [standard deviation (SD) 13] years, 71% female} with long COVID-19 (n = 17), raised troponin (n = 2), or unexplained new-onset heart failure (n = 2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment, were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers were performed. Nine of the 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and two had severe left ventricular (LV) impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23, and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T alpha beta cells showed higher proportions of cytotoxic granzyme B+(GZB+)-secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a least absolute shrinkage and selection operator regression model (composite area under the curve 0.96, 95% confidence interval 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r = 0.47, P = 0.04).Conclusion COVID-19-related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection. Graphical Abstract Summary of study methods and main findings.

While acute cardiovascular complications of COVID-19 are well-described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19. Twenty-one participants (mean age 47 [SD 13] years, 71% female) with long COVID (n=17), raised troponin (n=2), or unexplained new-onset heart failure (n=2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers was performed. Nine of 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and 2 had severe left ventricular impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23 and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T αβ cells showed higher proportions of cytotoxic granzyme B+ secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a LASSO regression model (composite AUC 0.96, 95%CI 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r=0.47, p=0.04). COVID-19 related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection.

AIMS:To assess pericoronary adipose tissue (PCAT) density on coronary computed tomography angiography (CCTA) as a marker of inflammatory disease activity in coronary allograft vasculopathy (CAV). METHODS AND RESULTS:PCAT density, lesion volumes, and total vessel volume-to-myocardial mass ratio (V/M) were retrospectively measured in 126 CCTAs from 94 heart transplant patients [mean age 49 (SD 14.5) years, 40% female] who underwent imaging between 2010 and 2021; age- and sex-matched controls; and patients with atherosclerosis. PCAT density was higher in transplant patients with CAV [n = 40; -73.0 HU (SD 9.3)] than without CAV [n = 86; -77.9 HU (SD 8.2)], and controls [n = 12; -86.2 HU (SD 5.4)], P < 0.01 for both. Unlike patients with atherosclerotic coronary artery disease (n = 32), CAV lesions were predominantly non-calcified and comprised of mostly fibrous or fibrofatty tissue. V/M was lower in patients with CAV than without [32.4 mm3/g (SD 9.7) vs. 41.4 mm3/g (SD 12.3), P < 0.0001]. PCAT density and V/M improved the ability to predict CAV from area under the receiver operating characteristic curve (AUC) 0.75-0.85 when added to donor age and donor hypertension status (P < 0.0001). PCAT density above -66 HU was associated with a greater incidence of all-cause mortality {odds ratio [OR] 18.0 [95% confidence interval (CI) 3.25-99.6], P < 0.01} and the composite endpoint of death, CAV progression, acute rejection, and coronary revascularization [OR 7.47 (95% CI 1.8-31.6), P = 0.01] over 5.3 (SD 2.1) years. CONCLUSION:Heart transplant patients with CAV have higher PCAT density and lower V/M than those without. Increased PCAT density is associated with adverse clinical outcomes. These CCTA metrics could be useful for the diagnosis and monitoring of CAV severity.

Introduction To assess pericoronary adipose tissue (PCAT) density on Computed Tomography Coronary Angiography (CTCA) as a marker of inflammatory disease activity in coronary allograft vasculopathy (CAV). Methods PCAT density, lesion volumes, and total vessel volume-to-myocardial mass ratio (V/M) were retrospectively measured in heart transplant patients, age and sex-matched controls, and patients with atherosclerosis. Results A total of 126 CTCAs were analysed from 94 heart transplant patients (mean age 49 [SD 14.5] years, 40% female). PCAT density was higher in transplant patients with CAV (n=40; -73.0 HU [SD 9.3]) than without CAV (n=86; -77.9 HU [SD 8.2]), and controls (n=12; -86.2 HU [SD 5.4]), p<0.01 for both (Fig-A). Unlike patients with atherosclerotic coronary artery disease (n=32), CAV lesions were non-calcified, comprising of mostly fibrous or fibrofatty tissue. V/M was lower in patients with CAV than without (32.4 mm3/g [SD 9.7] vs. 41.4 mm3/g [SD 12.3], p<0.0001). PCAT density and V/M improved the ability to predict CAV from AUC 0.75 to 0.85 when added to donor age and donor hypertension status (p<0.0001) (Fig-B). PCAT density above -66 HU was associated with a greater incidence of all-cause mortality (OR 18.0 [95%CI 3.25-99.6], p<0.01) and the composite endpoint of death, CAV progression, acute rejection (Fig-C), and coronary revascularization (OR 7.47 [95%CI 1.8-31.6], p=0.01) over 5.3 (SD 2.1) years. Conclusion Heart transplant patients with CAV have higher PCAT density and lower V/M than those without. Increased PCAT density is associated with adverse clinical outcomes. These CCTA metrics could be useful for CAV diagnosis and monitoring.

ostinfarct inflammation and its resolution modulate ischemic injury after myocardial infarction (MI). While cardiac magnetic resonance imaging (MRI) is useful for assessing ventricular function, viability, and struc-tural complications after MI, as well as detecting edema associated with acute inflammation, it lacks specificity for immune cell activity and may be less sensitive for identifying persistent, low-grade inflammation. Positron emission tomography (PET)

Attenuation correction methods in body PET/MRI do not consider lung density variations within and between participants, which can significantly affect PET image quantification in thoracic areas. We developed a hybrid ZTE-based/Dixon method for MR-based attenuation correction, which resulted in a pseudo-CT image (Dixon/pCT) and used for attenuation correction in the lung. PET images corrected with the Dixon/pCT attenuation map were compared to images produced with manufacturer’s Dixon attenuation map and a hybrid Dixon/CT image. Overall, the Dixon/pCT method reduced the absolute SUV error in the lung by 3%, when compared to the Dixon attenuation correction.

AbstractAimsTo examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis.Methods and resultsPCAT and PAAT density was measured in coronary (n = 1016) and aortic (n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P < 0.0001; PAAT: P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients (P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls (P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score (r = 0.43, P = 0.001) and C-reactive protein (r = 0.41, P < 0.0001) and was higher in active vs. inactive TAK (P = 0.002). mPCAT density above −74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97–1)]. The association of PCAT density and coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68Ga-DOTATATE maximum tissue-to-blood ratio (P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders.ConclusionsPCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK.

June 2020 1 Jason M. Tarkin , MD, PhD Christopher Wall, MD Deepa Gopalan, MD Luigi Aloj, MD Roido Manavaki, PhD Tim D. Fryer, PhD Eric O. Aboagye, MD, PhD Martin R. Bennett, MD, PhD James E. Peters, MD, PhD James H.F. Rudd, MD, PhD Justin C. Mason, MD, PhD Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an important diagnostic test for Takayasu arteritis (TAK),1 18F-FDG lacks inflammatory cell selectivity and cannot accurately distinguish arteritis from metabolically active vascular remodeling.2 This observation has led to the search for more sensitive and specific PET tracers for TAK. Macrophage activation antigen SST2 (somatostatin receptor subtype-2) PET represents a potential alternative imaging biomarker for defining disease activity in TAK, as macrophages are a major feature of the inflammatory infiltrate. We aimed to determine the ability of SST2 PET/magnetic resonance imaging (MRI) to detect arteritis in 2 patients with clinically active TAK.

To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases.

Positron emission tomography (PET) imaging is useful in cardiovascular disease across several areas, from assessment of myocardial perfusion and viability, to highlighting atherosclerotic plaque activity and measuring the extent of cardiac innervation in heart failure. Other important roles of PET have emerged in prosthetic valve endocarditis, implanted device infection, infiltrative cardiomyopathies, aortic stenosis and cardio-oncology. Advances in scanner technology, including hybrid PET/MRI and total body PET imaging, as well as the development of novel PET tracers and cardiac-specific postprocessing techniques using artificial intelligence will undoubtedly continue to progress the field.

Abstract Background Coronary artery disease (CAD) is an under-recognized complication of intense arterial inflammation in Takayasu arteritis (TAK). While pericoronary adipose tissue (PCAT) density is associated with arterial inflammation in CAD patients, this relationship has not previously been studied in TAK patients, nor directly compared with coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET). Purpose To compare PCAT density with clinical, biochemical and molecular imaging markers of inflammation in TAK and CAD patients. Methods PCAT density was quantified from computed tomography coronary angiography (CTCA) around each of the 17 coronary segments in patients with: (1) TAK and CAD, (2) atherosclerotic CAD, and (3) age and gender-matched healthy controls, using semi-automated software (Autoplaque). In TAK patients, PCAT density was compared to the Indian Takayasu Clinical Activity Score (ITAS) and high-sensitivity C-reactive protein (CRP). In CAD patients, PCAT density was compared to local arterial inflammation measured by coronary motion-frozen 68Ga-DOTATATE PET using image registration software (FusionQuant), and systemic (aortic) inflammation using 18F-fluorodeoxyglucose (FDG) PET. Data was acquired either during routine clinical care or prior research that established 68Ga-DOTATATE as an experimental marker of arterial inflammation that binds macrophage somatostatin receptor-2 in atherosclerotic plaques (NCT02021188). Results 60 patients were included (TAK, n=20; CAD, n=20; healthy, n=20). Non-calcified plaque burden (TAK: 95.2%; CAD: 90.4%, p<0.0001) and CRP (TAK: 25.2 ±SD 16.1 mg/L; CAD: 2.5 ±SD 1.7 mg/L, p=0.04) were greater in TAK than CAD patients. PCAT density varied significantly among the three groups (median [IQR] TAK: −72.9 [−81.2 to -66.1] Hounsfield unit [HU]; CAD: −79.9 [−88.0 to −72.2]; healthy: −83.8 [−90.1 to −75.8] HU, p<0.0001). Figure: box-plot showing the distribution of PCAT values by group, with corresponding representative multiplanar reconstructed and cross-sectional CTCA images with surrounding PCAT density displayed by color table in left anterior descending arteries. PCAT density was significantly associated with ITAS (r=0.61, p=0.004) and CRP (r=0.43, p=0.03) in TAK patients, and coronary 68Ga-DOTATATE maximum tissue-to-blood ratio (r=0.31, p<0.001) in CAD patients. PCAT density was not associated with aortic 18F-FDG uptake in CAD patients, nor subcutaneous (pre-sternal) adipose tissue density in either disease group. No significant patient-level confounders were identified using linear mixed-effects regression modelling. Conclusion PCAT density measured by CTCA is greater in TAK than CAD patients, and is associated with clinical and biochemical markers of disease activity in TAK, and coronary arterial inflammation measured by 68Ga-DOTATATE PET in CAD. PCAT could be a useful, easy to measure marker of coronary inflammation and disease activity in both TAK and CAD. PCAT density is greater in TAK than CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Wellcome Trust

AIMS:To assess the impact of the introduction of direct oral anticoagulants upon the outcomes from elective electrical cardioversion for atrial fibrillation.METHODS:This is a retrospective comparison of delay to elective cardioversion with different anticoagulants. The data was gathered from a large regional hospital from January 2013 to September 2017. There were 3 measured outcomes: 1) the time in weeks from referral to the date of attempted electrical cardioversion; 2) the proportion of patients who were successfully cardioverted; and 3) the proportion of patients who remained in sinus rhythm by the 12 week follow-up. Time-to-cardioversion was non-parametrically distributed so was analysed with Kruskal-Wallis testing and Mann-Whitney-U testing. Maintenance of sinus rhythm was analysed using z-testing.RESULTS:1,374 patients were submitted to cardioversion. The referrals for cardioversion were either from primary care or from cardiologists. At the time of cardioversion, 789 cases were anticoagulated on warfarin (W), 215 on apixaban (A) and 370 on rivaroxaban (R). All 3 cohorts were initially compared independently using Kruskal-Wallis testing. This demonstrated a significant difference in the delay (measured in weeks) between the A and W group (A = 7, W = 9, P<0.00001); the R and W group (R = 7, W = 9, P<0.00001) and no difference between R and A (A = 7, R = 7, P = 0.92). As there was no difference between the A and R groups, they were combined to form the AR group. The AR group was compared to the W group using Mann-Whitney-U testing which demonstrated a significant delay between the groups (AR = 7, W = 9, P<0.00001). Excluding patients with prior or unknown attempts of cardioversion (n = 791), the W patients (n = 152) were less successful in achieving sinus rhythm at cardioversion than the AR (n = 431) group (W = 95% vs AR = 99% P = 0.04). However at 12 weeks, incidence of sinus rhythm was significantly different (W = 40% vs AR = 49% P = 0.049). These groups were compared by z testing. At 12 weeks' follow-up there was no statistical difference in rate of adverse consequences between the AR group and the W group, but the rate of adverse consequences was too low to draw further conclusions.CONCLUSION:DOACs appear to significantly shorten the latency between the decision to cardiovert and the cardioversion procedure by at least 2 weeks compared to warfarin in a real-world setting. In this study, patients who had not previously been cardioverted who were anticoagulated with warfarin had a significantly lower probability of conversion to sinus rhythm and a significantly lower probability to remain in sinus rhythm at the 12 week follow-up compared to the combined apixaban and rivaroxaban group.

DNA-RNA hybrids arise in all cell types, and are removed by multiple enzymes, including the trimeric ribonuclease, RNase H2. Mutations in human RNase H2 result in Aicardi–Goutières syndrome (AGS), an inflammatory brain disorder notable for being a Mendelian mimic of congenital viral infection. Previous studies have shown that several AGS-associated mutations of the RNase H2B subunit do not affect trimer stability or catalytic activity and are clustered on the surface of the complex, leading us to speculate that these mutations might impair important interactions of RNase H2 with so far unidentified proteins. In this study, we show that AGS mutations in this cluster impair the interaction of RNase H2 with several members of the CoREST chromatin-silencing complex that include the histone deacetylase HDAC2 and the demethylase KDM1A, the transcriptional regulators RCOR1 and GTFII-I as well as ZMYM3, an MYM-type zinc finger protein. We also show that the interaction is mediated by the zinc finger protein ZMYM3, suggesting that ZMYM3 acts as a novel type of scaffold protein coordinating interactions between deacetylase, demethylase and RNase H type enzymes, raising the question of whether coordination between histone modifications and the degradation of RNA-DNA hybrids may be required to prevent inflammation in humans.