278 results found
Patel K, Jones T, Sattler S, et al., 2020, Pro-arrhythmic electrophysiological and structural remodelling in rheumatoid arthritis, American Journal of Physiology: Heart and Circulatory Physiology, ISSN: 0363-6135
Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a two-fold increase in the incidence of sudden cardiac death (SCD) compared to the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischaemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodelling in response to chronic inflammation in RA. In particular, it focuses on the roles of non-ischaemic structural remodelling, altered cardiac ionic currents and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.
Herrick AL, Griffiths-Jones DJ, Ryder WD, et al., 2020, Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis (PRedSS), Journal of Scleroderma and Related Disorders, Pages: 1-8, ISSN: 2397-1983
Background:Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function.Methods:PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness.Results:Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited.Conclusion:PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis.
Seneviratne A, Han Y, Wong E, et al., 2020, Hematoma resolution in vivo is directed by Activating Transcription Factor 1 (ATF1), Circulation Research, Vol: 127, Pages: 928-944, ISSN: 0009-7330
Rationale: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an adenosine monophosphate activated protein kinase / activating transcription factor 1 (AMPK/ATF1) pathway that directs Mhem macrophages through coregulation of heme oxygenase 1 (HMOX1, HO-1) and lipid homeostasis genes.Objective: We asked whether this pathway had an in vivo role in mice.Methods and Results: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow derived macrophages (mBMM), heme induced HO-1, lipid regulatory genes including LXR, the growth factor IGF1, and the splenic red pulp macrophage gene Spic. This response was lost in mBMM from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between day 8 and day 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-) (n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent.Conclusions: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution.
Corovic A, Wall C, Mason JC, et al., 2020, Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation, CURRENT CARDIOLOGY REPORTS, Vol: 22, ISSN: 1523-3782
Porter A, Mason JC, 2020, Intervention in Takayasu aortitis: when, where and how?, Hearts, Vol: 1, Pages: 62-74
Takayasu arteritis is a large vessel vasculitis which commonly affects the aorta and its major branches. Active arterial inflammation is characterised by the presence of T and B lymphocytes, natural killer cells, macrophages and occasional multinucleate giant cells. Uncontrolled vascular inflammation can progress to cause arterial stenosis, occlusion or aneurysmal dilatation. Medical treatment involves combination immunosuppression and more recently biologic therapies targeting TNF-α and IL-6. Due to the typical delays in diagnosis and accumulation of arterial injury, open and endovascular surgical intervention are important and potentially life-saving treatment options for Takayasu arteritis. Common indications for surgery include aortic coarctation and ascending aortic dilatation ± aortic valve regurgitation, renal artery stenosis, ischaemic heart disease, supra-aortic disease, mesenteric ischaemia, severe limb-threatening claudication and aneurysm repair. Surgical outcomes are markedly improved in patients with clinically inactive disease and those who receive adequate periprocedural immunosuppression. Decisions regarding surgical approaches are best made as part of a multi-disciplinary team.
Evans PC, Ed Rainger G, Mason JC, et al., 2020, Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science, Cardiovascular Research, ISSN: 0008-6363
The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.
Boyle J, Seneviratne A, Cave L, et al., 2020, Metformin directly suppresses atherosclerosis in normoglycemic mice via haematopoietic Adenosine Monophosphate-Activated Protein Kinase (AMPK), Cardiovascular Research, ISSN: 0008-6363
AimsAtherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque hemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and ATF1. The anti-diabetic drug metformin may also activate AMPK-dependent signalling.HypothesisMetformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, and thereby suppresses atherogenesis.Methods and ResultsNormoglycemic Ldlr-/- hyperlipidemic mice were treated with oral metformin, which profoundly suppressed atherosclerotic lesion development (p < 5x10−11). Bone marrow transplantation from AMPK-deficient mice demonstrated that metformin-related atheroprotection required haematopoietic AMPK (ANOVA, p < 0.03). Metformin at a clinically relevant concentration (10μM) evoked AMPK-dependent and ATF1-dependent increases in Hmox1, Nr1h2 (Lxrb), Abca1, Apoe, Igf1 and Pdgf, increases in several M2-markers and decreases in Nos2, in murine bone marrow macrophages. Similar effects were seen in human blood-derived macrophages, in which metformin induced protective genes and M2-like genes, suppressible by si-ATF1-mediated knockdown. Microarray analysis comparing metformin with heme in human macrophages indicated that the transcriptomic effects of metformin were related to those of heme, but not identical. Metformin induced lesional macrophage expression of p-AMPK, p-ATF1 and downstream M2-like protective effects.ConclusionMetformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, and results in highly suppressed atherogenesis in hyperlipidemic mice via haematopoietic AMPK.Translational perspectiveThe work shows that oral antidiabetic drug metformin may suppress atherosclerotic lesion development via hematopoietic AMPK at clinically relevant concentrations, rather than via a hypoglycemic effect. Activating Transcription Factor 1 (ATF1) may mediate induction of key atheroprotective genes
Khawaja AA, Maughan RT, Paschalaki KE, et al., 2020, Modelling endothelial function in vitro and via blood sampling to assess cardiovascular risk in people living with HIV, Publisher: JOHN WILEY & SONS LTD, Pages: 105-105
Tarkin JM, Wall C, Gopalan D, et al., 2020, Novel approach to imaging active takayasu arteritis using somatostatin receptor positron emission tomography/magnetic resonance imaging., Circulation: Cardiovascular Imaging, Vol: 13, Pages: 1-3, ISSN: 1941-9651
Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an important diagnostic test for Takayasu arteritis (TAK),118F-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.
Porter A, Youngstein T, Tombetti E, et al., 2020, Biologic therapy in supra-aortic Takayasu arteritis can improve symptoms of cerebral ischaemia without surgical intervention, Rheumatology, Vol: 59, Pages: iii28-iii32, ISSN: 0080-2727
Background: Takayasu arteritis typically results in severe arterial injury with stenoses, occlusions and occasionally aneurysms. Involvement of the supra-aortic arteries is common, and in its most severe form may compromise cerebral blood supply, resulting in signs of cerebral ischaemia including visual impairment, dysphasia, hemiparesis, loss of consciousness and stroke. In addition to combination immunosuppression, the management paradigm for symptomatic cerebral ischaemia includes revascularisation. The invasive nature of this surgery, the risk of complications and the relatively high rate of re-stenosis is of concern to patients and physicians alike.The aim of this study was to determine whether combined immunosuppression with early escalation to biologic therapy improved outcomes and reduced the need for high risk surgical intervention Methods: A retrospective review of 145 Takayasu arteritis patients attending Imperial College Healthcare between 2010-2018 was conducted to identify those with cerebral ischaemia secondary to supra-aortic disease and to analyse their treatment and outcomes. Results: Eight patients (5.5%) were identified. Seven received long-term combined immunosuppressive therapy and six were prescribed biologics. The data revealed a higher than expected comprehensive response to therapy, with significant falls in disease activity, cerebral ischaemia score and prednisolone dose required, over a median follow-up of 37 months. Serial imaging analysis detected no arterial disease progression after the initiation of optimal therapy. Only one patient required surgical intervention for persistent neurological symptoms. Conclusion: Early use of biologic therapy in those with supra-aortic Takayasu arteritis presenting with cerebral ischaemia may reduce the numbers of patients requiring surgical intervention and improve outcomes.
Mason J, 2020, The impact of integrated non-invasive imaging in the management of takayasu arteritis, JACC: Cardiovascular Imaging, ISSN: 1876-7591
Dahanayake C, Maughan R, Youngstein T, et al., 2020, ASSESSING THE SAFETY OF TREATMENT CESSATION IN TAKAYASU ARTERITIS, Annual Conference of the British-Society-for-Rheumatology (BSR), Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324
Dufton NP, Peghaire CR, Osuna-Almagro L, et al., 2020, Dynamic regulation of canonical TGF beta signalling by endothelial transcription factor ERG protects from liver fibrogenesis (vol 31, pg 450, 2017), NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Mackie SL, Dejaco C, Appenzeller S, et al., 2020, British Society for Rheumatology guideline on diagnosis and treatment of giant cell arteritis: executive summary, RHEUMATOLOGY, Vol: 59, Pages: 487-494, ISSN: 1462-0324
Mackie SL, Dejaco C, Appenzeller S, et al., 2020, British Society for Rheumatology guideline on diagnosis and treatment of giant cell arteritis., Rheumatology, Vol: 59, Pages: e1-e23, ISSN: 1462-0324
Tarkin JM, Cole GD, Gopalan D, et al., 2020, Multimodal imaging of granulomatosis with polyangiitis aortitis complicated by severe aortic regurgitation and complete heart block, Circulation: Cardiovascular Imaging, Vol: 13, Pages: 1-3, ISSN: 1941-9651
Tarkin JM, Gopalan D, Mason JC, 2020, A woman in her 20s with chest pain and arm claudication., JAMA Cardiology, ISSN: 2380-6583
Tarkin J, Wall C, Gopalan D, et al., A novel approach to imaging active Takayasu arteritis using somatostatin receptor PET/MRI ligands, Circulation: Cardiovascular Imaging, ISSN: 1941-9651
Mackie SL, Dejaco C, Appenzeller S, et al., BSR guideline on diagnosis and treatment of giant cell arteritis, Rheumatology, ISSN: 1462-0324
Tarkin JM, Mason JC, Fayad ZA, 2019, Imaging at the inter-face of inflammation and angiogenesis by F-18-fluciclatide PET, Heart, Vol: 105, Pages: 1845-1847, ISSN: 1355-6037
Peghaire C, Dufton N, Lang M, et al., 2019, The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature, Nature Communications, Vol: 10, ISSN: 2041-1723
Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anti-coagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed- specific anti-coagulant pathway in microvasculature exposed to low SS.
Fourre J, Bardi I, Maughan RT, et al., 2019, Endothelial cell activation by pro-inflammatory cytokines exerts novel paracrine effects on co-cultured cardiomyocytes, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3904-3904, ISSN: 0195-668X
Poo SX, Tham CSW, Smith C, et al., 2019, IgG4-related disease in a multi-ethnic community: Clinical characteristics and association with malignancy, QJM: An International Journal of Medicine, Vol: 112, Pages: 763-769, ISSN: 1460-2393
BackgroundImmunoglobulin-G4-related disease (IgG4-RD) is a recently recognised fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood.AimTo describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy.DesignRetrospective analysis of case-note and electronic data.MethodsCases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using ‘IgG4’ or ‘inflammatory pseudotumour’ as search terms. Electronic records, imaging and histopathology reports were reviewed.Results66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response, however 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, 7 patients subsequently relapsed after a mean duration of 11 months and 4 progressed despite treatment.ConclusionsWe report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.
Boyle J, Seneviratne A, Hyde G, et al., 2019, METFORMIN DIRECTLY SUPPRESSES ATHEROSCLEROSIS IN NORMOGLYCEMIC MICE VIA HAEMATOPOIETIC ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE (AMPK), 87th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E45-E46, ISSN: 0021-9150
Boyle J, Seneviratne A, Han Y, et al., 2019, VERTEBRATE HEMATOMA RESOLUTION IS DIRECTED BY ACTIVATING TRANSCRIPTION FACTOR 1 (ATF1) AND ADENOSINE-MONOPHOSPHATE-ACTIVATED-PROTEIN-KINASE (AMPK), 87th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E246-E246, ISSN: 0021-9150
Coath F, Gillbert K, Griffiths B, et al., 2019, Corrigendum: Giant cell arteritis: new concepts, treatments and the unmet need that remains, Rheumatology, Vol: 58, Pages: 1123-1125, ISSN: 1462-0324
This is a correction to: Rheumatology, Volume 58, Issue 7, July 2019, Pages 1123–1125, https://doi.org/10.1093/rheumatology/key326
Coath F, Gillbert K, Hall F, et al., 2019, Giant cell arteritis: new concepts, treatments and the unmet need that remains, Rheumatology, Vol: 58, Pages: 1123-1125, ISSN: 1462-0324
Nadkarni S, Lashin H, Hollywood J, et al., 2019, Identification of an activated neutrophil phenotype in polymyalgia rheumatica during steroid treatment: a potential involvement of immune cell cross-talk, Clinical Science, Vol: 133, Pages: 839-851, ISSN: 0143-5221
We have reported the existence of a distinct neutrophil phenotype in giant cell arteritis (GCA) patients arising at week 24 of steroid treatment. In the present study, we investigated whether longitudinal analysis of neutrophil phenotype in patients with polymyalgia rheumatica (PMR) could reveal a novel association with disease status and immune cell cross-talk. Thus, we monitored PMR patient neutrophil phenotype and plasma microvesicle (MV) profiles in blood aliquots collected pre-steroid, and then at weeks 1, 4, 12 and 24 post-steroid treatment.Using flow cytometric and flow chamber analyses, we identified 12-week post-steroid as a pivotal time-point for a marked degree of neutrophil activation, correlating with disease activity. Analyses of plasma MVs indicated elevated AnxA1+ neutrophil-derived vesicles which, in vitro, modulated T-cell reactivity, suggesting distinct neutrophil phenotypic and cross-talk changes at 24 weeks, but not at 12-week post-steroid.Together, these data indicate a clear distinction from GCA patient neutrophil and MV signatures, and provide an opportunity for further investigations on how to ‘stratify’ PMR patients and monitor their clinical responses through novel use of blood biomarkers.
Shah K, Mason JC, 2019, REAL LIFE EXPERIENCE OF TOCILIZUMAB FOR TAKAYASU ARTERITIS, Annual Conference of the British-Soceity-for-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 158-158, ISSN: 1462-0324
Mason J, Olabi B, Farah Z, 2019, Cutaneous polyarteritis nodosa presenting atypically with severe pharyngeal ulceration, Case Reports in Rheumatology, Vol: 2019, ISSN: 2090-6889
Polyarteritis nodosa (PAN) is a multisystem, necrotising vasculitis of small- and medium-sized arteries with a predilection for the visceral vessels. Cutaneous PAN is a rare variant with symptomatic vasculitis limited to the skin, typically presenting as nodular lesions on the extremities with a propensity to ulcerate. We describe a rare case of histologically confirmed cutaneous PAN presenting in a 55-year-old Ghanaian woman with severe oropharyngeal ulceration. This was associated with dysphagia and significant weight loss. Oesophagoduodenoscopy showed that the ulceration extended throughout the oropharynx. Systemic polyarteritis nodosa was ruled out with magnetic resonance angiography. Our patient was treated successfully with corticosteroids and methotrexate. This case suggests that cutaneous PAN should be considered in the differential diagnosis of patients with oropharyngeal ulceration and that histological assessment is pivotal in establishing the diagnosis early in order to instigate appropriate therapy.
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