Publications
424 results found
Dong J, Lim W-W, Shekeran SG, et al., 2022, Hepatocyte specific gp130 signalling underlies APAP induced liver injury, International Journal of Molecular Sciences, Vol: 23, Pages: 1-16, ISSN: 1422-0067
N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1β, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.
Tayal U, Verdonschot JAJ, Hazebroek MR, et al., 2022, Precision phenotyping of dilated cardiomyopathy using multidimensional data., Journal of the American College of Cardiology, Vol: 79, Pages: 2219-2232, ISSN: 0735-1097
BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to trad
Zhou J, Tripathi M, Ho JP, et al., 2022, Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis, THYROID, Vol: 32, Pages: 725-738, ISSN: 1050-7256
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- Citations: 21
Mia MM, Cibi DM, Ghani SABA, et al., 2022, Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function, Cardiovascular Research, Vol: 118, Pages: 1785-1804, ISSN: 0008-6363
AimsFibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established.Methods and resultsUsing mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response.ConclusionWe demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts prolifera
Ng B, Viswanathan S, Widjaja AA, et al., 2022, IL11 activates pancreatic stellate cells and causes pancreatic inflammation, fibrosis and atrophy in a mouse model of pancreatitis, International Journal of Molecular Sciences, Vol: 23, Pages: 1-17, ISSN: 1422-0067
Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.
Widjaja AA, Shekeran SG, Adami E, et al., 2022, A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 33, Pages: 718-730, ISSN: 1046-6673
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- Citations: 11
Tayal U, gregson J, Buchan R, et al., 2022, Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy, Heart, Vol: 108, Pages: 619-625, ISSN: 1355-6037
Objective The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. Methods Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrollment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared to patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group– n =92, 94% vs n =306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in mid-wall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 0.73 to 2.26, p=0.38) during median follow up of 3.9 years. ConclusionDilated cardiomyopathy patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with dilated cardiomyopathy.
Lim W-W, Dong J, Ng B, et al., 2022, Inhibition of IL11 signaling reduces aortic pathology in murine Marfan syndrome, Circulation Research, Vol: 130, Pages: 728-740, ISSN: 0009-7330
Background:Marfan syndrome (MFS) is associated with TGF (transforming growth factor) β–stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFβ induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta.Methods:We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in Fbn1C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11EGFP/+) reporter strain or to a strain deleted for the IL11 receptor (Il11ra1−/−). In therapeutic studies, mMFS were administered an X209 (neutralizing antibody against IL11RA [IL11 receptor subunit alpha]) or IgG for 20 weeks and imaged longitudinally.Results:IL11 mRNA and protein were elevated in the aortas of mMFS mice, as compared to controls. mMFS mice crossed to Il11EGFP/+ mice had increased IL11 expression in VSMCs, notably in the aortic root and ascending aorta. As compared to the mMFS parental strain, double mutant mMFS:Il11ra1−/− mice had reduced aortic dilatation and exhibited lesser fibrosis, inflammation, elastin breaks, and VSMC loss, which was associated with reduced aortic COL1A1 (collagen type I alpha 1 chain), IL11, MMP2/9, and phospho-ERK expression. To explore therapeutic targeting of IL11 signaling in MFS, we administered either a neutralizing antibody against IL11RA (X209) or an IgG control. After 20 weeks of antibody administration, as compared to IgG, mMFS mice receiving X209 had reduced thoracic and abdominal aortic dilation as well as lesser fibrosis, inflammation, elastin breaks, and VSMC loss. By immunoblotting, X209 was shown to reduce aortic COL1A1, IL11, MMP2/9, and phospho-E
Rauseo E, Omer M, Amir-Khalili A, et al., 2022, A systematic quality scoring analysis to assess automated cardiovascular magnetic resonance segmentation algorithms, Frontiers in Cardiovascular Medicine, Vol: 8, ISSN: 2297-055X
Background: The quantitative measures used to assess the performance of automated methods often do not reflect the clinical acceptability of contouring. A quality-based assessment of automated cardiac magnetic resonance (CMR) segmentation more relevant to clinical practice is therefore needed.Objective: We propose a new method for assessing the quality of machine learning (ML) outputs. We evaluate the clinical utility of the proposed method as it is employed to systematically analyse the quality of an automated contouring algorithm.Methods: A dataset of short-axis (SAX) cine CMR images from a clinically heterogeneous population (n = 217) were manually contoured by a team of experienced investigators. On the same images we derived automated contours using a ML algorithm. A contour quality scoring application randomly presented manual and automated contours to four blinded clinicians, who were asked to assign a quality score from a predefined rubric. Firstly, we analyzed the distribution of quality scores between the two contouring methods across all clinicians. Secondly, we analyzed the interobserver reliability between the raters. Finally, we examined whether there was a variation in scores based on the type of contour, SAX slice level, and underlying disease.Results: The overall distribution of scores between the two methods was significantly different, with automated contours scoring better than the manual (OR (95% CI) = 1.17 (1.07–1.28), p = 0.001; n = 9401). There was substantial scoring agreement between raters for each contouring method independently, albeit it was significantly better for automated segmentation (automated: AC2 = 0.940, 95% CI, 0.937–0.943 vs manual: AC2 = 0.934, 95% CI, 0.931–0.937; p = 0.006). Next, the analysis of quality scores based on different factors was performed. Our approach helped identify trends patterns of lower segmentation quality as observed for left ventricle epicardial and basal contours with both methods.
Clerk A, Meijles DN, Hardyman MA, et al., 2022, Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo, Biochemical Journal, Vol: 479, Pages: 401-424, ISSN: 0264-6021
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.
Osimo E, Sweeney M, De Marvao A, et al., 2021, Adipose tissue dysfunction, inflammation, and insulin resistance: alternative pathways to cardiac remodelling in schizophrenia. A multimodal, case-control study, Translational Psychiatry, Vol: 11, Pages: 1-9, ISSN: 2158-3188
Cardiovascular diseases are the leading cause of death in schizophrenia. Patients with schizophrenia show evidence of concentric cardiac remodelling (CCR), defined as an increase in left-ventricular mass over end-diastolic volumes. CCR is a predictor of cardiac disease, but the molecular pathways leading to this in schizophrenia are unknown. We aimed to explore the relevance of hypertensive and non-hypertensive pathways to CCR and their potential molecular underpinnings in schizophrenia. In this multimodal case–control study, we collected cardiac and whole-body fat magnetic resonance imaging (MRI), clinical measures, and blood levels of several cardiometabolic biomarkers known to potentially cause CCR from individuals with schizophrenia, alongside healthy controls (HCs) matched for age, sex, ethnicity, and body surface area. Of the 50 participants, 34 (68%) were male. Participants with schizophrenia showed increases in cardiac concentricity (d = 0.71, 95% CI: 0.12, 1.30; p = 0.01), indicative of CCR, but showed no differences in overall content or regional distribution of adipose tissue compared to HCs. Despite the cardiac changes, participants with schizophrenia did not demonstrate activation of the hypertensive CCR pathway; however, they showed evidence of adipose dysfunction: adiponectin was reduced (d = −0.69, 95% CI: −1.28, −0.10; p = 0.02), with evidence of activation of downstream pathways, including hypertriglyceridemia, elevated C-reactive protein, fasting glucose, and alkaline phosphatase. In conclusion, people with schizophrenia showed adipose tissue dysfunction compared to body mass-matched HCs. The presence of non-hypertensive CCR and a dysmetabolic phenotype may contribute to excess cardiovascular risk in schizophrenia. If our results are confirmed, acting on this pathway could reduce cardiovascular risk and resultant life-years lost in people with schizophrenia.
Adami E, Viswanathan S, Widjaja AA, et al., 2021, IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGF beta-mediated activation of dermal fibroblasts, Rheumatology, Vol: 60, Pages: 5820-5826, ISSN: 1462-0324
ObjectivesInterleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls.MethodsWe measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping.ResultsIn patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK.ConclusionsThese data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.
Lota AS, Tsao A, Owen R, et al., 2021, Prognostic significance of non-ischaemic patterns of myocardial fibrosis in patients with normal left ventricular volumes and ejection fraction – the FINALIZE study, JACC: Cardiovascular Imaging, Vol: 14, Pages: 2353-2365, ISSN: 1876-7591
Background: Non-ischaemic patterns of late gadolinium enhancement (LGE) with normal left ventricular volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance (CMR) but their prognostic significance, and consequently management, is uncertain. Objectives: To investigate the prognostic significance of LGE in patients without coronary artery disease and with normal range LV volumes and ejection fraction. Methods: Patients with mid-wall/subepicardial LGE and normal LV volumes, wall thickness and ejection fraction on CMR were enrolled and compared to a control group without LGE.57 The primary outcome was actual or aborted sudden cardiac death (SCD). Results: Of 748 patients enrolled, 401 had LGE and 347 did not. Median age was 50 years (IQR 38-61), LV ejection fraction 66% (IQR 62-70) and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). Nopatient experienced SCD and only one LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3years, thirty patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; p=0.71) and was associated with age (H 2.04 per 10-years; 95%CI 1.46-2.79; p<0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned CV hospitalisation (HR 7.22; 95%CI 4.26-21.17; p<0.0001). Conclusion: There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location or extent, although the latter was associated with greater CV hospitalisation for suspected myocarditis and symptomatic ventricular tachycardia.
Schumacher D, Liehn EA, Nilcham P, et al., 2021, A neutralizing IL-11 antibody reduces vessel hyperplasia in a mouse carotid artery wire injury model, Scientific Reports, Vol: 11, ISSN: 2045-2322
Vascular restenosis remains a major problem in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Neointimal hyperplasia, defined by post-procedure proliferation and migration of vascular smooth muscle cells (VSMCs) is a key underlying pathology. Here we investigated the role of Interleukin 11 (IL-11) in a mouse model of injury-related plaque development. Apoe-/- mice were fed a hyperlipidaemic diet and subjected to carotid wire injury of the right carotid. Mice were injected with an anti-IL11 antibody (X203), IgG control antibody or buffer. We performed ultrasound analysis to assess vessel wall thickness and blood velocity. Using histology and immunofluorescence approaches, we determined the effects of IL-11 inhibition on VSMC and macrophages phenotypes and fibrosis. Treatment of mice with carotid wire injury using X203 significantly reduced post-endothelial injury vessel wall thickness, and injury-related plaque, when compared to control. Immunofluorescence staining of the injury-related plaque showed that X203 treatment did not reduce macrophage numbers, but reduced the number of VSMCs and lowered matrix metalloproteinase 2 (MMP2) levels and collagen content in comparison to control. X203 treatment was associated with a significant increase in smooth muscle protein 22α (SM22α) positive cells in injury-related plaque compared to control, suggesting preservation of the contractile VSMC phenotype. Interestingly, X203 also reduced the collagen content of uninjured carotid arteries as compared to IgG, showing an additional effect on hyperlipidemia-induced arterial remodeling in the absence of mechanical injury. Therapeutic inhibition of IL-11 reduced vessel wall thickness, attenuated neointimal hyperplasia, and has favorable effects on vascular remodeling following wire-induced endothelial injury. This suggests IL-11 inhibition as a potential novel therapeutic approach to reduce arterial stenosis following revascularization in
Wang S, Qin C, Savioli N, et al., 2021, Joint motion correction and super resolution for cardiac segmentationvia latent optimisation, International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI), Publisher: Springer, Pages: 14-24
In cardiac magnetic resonance (CMR) imaging, a 3D high-resolution segmentation of the heart is essential for detailed description of its anatomical structures. However, due to the limit of acquisition duration andrespiratory/cardiac motion, stacks of multi-slice 2D images are acquired inclinical routine. The segmentation of these images provides a low-resolution representation of cardiac anatomy, which may contain artefacts caused by motion. Here we propose a novel latent optimisation framework that jointly performs motion correction and super resolution for cardiac image segmentations. Given a low-resolution segmentation as input, the framework accounts for inter-slice motion in cardiac MR imaging and super-resolves the input into a high-resolution segmentation consistent with input. A multi-view loss is incorporated to leverage information from both short-axis view and long-axis view of cardiac imaging. To solve the inverse problem, iterative optimisation is performed in a latent space, which ensures the anatomical plausibility. This alleviates the need of paired low-resolution and high-resolution images for supervised learning. Experiments on two cardiac MR datasets show that the proposed framework achieves high performance, comparable to state-of-the-art super-resolution approaches and with better cross-domain generalisability and anatomical plausibility.
Widjaja AA, Viswanathan S, Jinrui D, et al., 2021, Molecular dissection of pro-fibrotic IL11 signaling in cardiac and pulmonary fibroblasts, Frontiers in Molecular Biosciences, Vol: 8, ISSN: 2296-889X
In fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in <jats:italic>Il11ra1</jats:italic> null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.
Dong J, Viswanathan S, Adami E, et al., 2021, The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling, eLife, Vol: 10, Pages: 1-16, ISSN: 2050-084X
It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.
Simoes Monteiro de Marvao A, McGurk K, Zheng S, et al., 2021, Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy, Journal of the American College of Cardiology, Vol: 78, Pages: 1097-1110, ISSN: 0735-1097
Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomereencoding genes, but little is known about the clinical significance of these variants in thegeneral population.Objectives: To compare lifetime outcomes and cardiovascular phenotypes according to thepresence of rare variants in sarcomere-encoding genes amongst middle-aged adults.Methods: We analysed whole exome sequencing and cardiac magnetic resonance (CMR)imaging in UK Biobank participants stratified by sarcomere-encoding variant status.Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associatedsarcomere-encoding genes in 200,584 participants was 2.9% (n=5,712; 1 in 35), and theprevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was0.25% (n=493, 1 in 407). SARC-HCM-P/LP variants were associated with increased risk ofdeath or major adverse cardiac events compared to controls (HR 1.69, 95% CI 1.38 to 2.07,p<0.001), mainly due to heart failure endpoints (HR 4.23, 95% CI 3.07 to 5.83, p<0.001). In21,322 participants with CMR, SARC-HCM-P/LP were associated with asymmetric increasein left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) buthypertrophy (≥13mm) was only present in 18.4% (n=9/49, 95% CI 9 to 32%). SARC-HCMP/LP were still associated with heart failure after adjustment for wall thickness (HR 6.74,95% CI 2.43 to 18.7, p<0.001).Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have lowaggregate penetrance for overt HCM but are associated with increased risk of adversecardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absoluteevent rates are low, identification of these variants may enhance risk stratification beyondfamilial disease.
Le T-T, Huang B, Pua CJ, et al., 2021, Lowering the recommended maximal wall thickness threshold improves diagnostic sensitivity in Asians with hypertrophic cardiomyopathy, JACC: Asia, Vol: 1, Pages: 218-226, ISSN: 2772-3747
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established that Asians have smaller hearts than do Caucasians. OBJECTIVES: This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians. METHODS: The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments. RESULTS: Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P < 0.001). Conversely, WTMax was similar between male and female patients with HCM (15.2 ± 3.4 mm vs 14.7 ± 3.0 mm, respectively; P = 0.484) and between those with and without a pathogenic gene variant (P = 0.828). Using the recommended diagnostic threshold of 15.0 mm, 56 patients with HCM had WTMax <15.0 mm and no healthy volunteers had WTMax >15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain. CONCLUSIONS: The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMa
Viswanathan S, Ng B, Widjaja AA, et al., 2021, Critical Conditions for Studying Interleukin-11 Signaling In Vitro and Avoiding Experimental Artefacts., Curr Protoc, Vol: 1
Interleukin (IL) 11 is a member of the IL6 family of cytokines which require the ubiquitous gp130 receptor to activate canonical (JAK/STAT) and non-canonical (e.g., ERK) signaling pathways. The IL11 cytokine is upregulated in a number of fibro-inflammatory diseases and cancer, where it binds the cognate IL11 receptor alpha subunit (IL11RA) to form a hexameric IL11:IL11RA:gp130 signaling complex. The specific IL11RA receptor is highly expressed on cells of the stromal and parenchymal niche but expressed at low levels on immune cells, highly passaged cells, or transformed cell lines. Consequently, primary cells such as hepatic stellate cells, fibroblasts, and hepatocytes are ideal experimental systems to study IL11 signaling in vitro. In contrast to immortalized cell lines, primary cells better display relevant cellular physiology and pathobiology. This collection of protocols details experimental and culturing conditions for primary cells that preserve meaningful cellular states and physiological responses ex vivo in conventional 2D cell culture systems. Readouts of cellular activity are chosen carefully to capture the non-canonical, post-transcriptional activity of IL11 signaling. Our data suggest that cell type, cell culture conditions, passage number, concentrations of stimuli, timing, and other factors have major implications for studies of IL11 signaling. In vitro experiments with primary cell material need to be planned and executed with great caution. Otherwise, physiologically relevant mechanisms may become dysfunctional and reproducible experimental artefacts can obscure our view of true cytokine biology. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Expansion of primary human hepatic stellate cells (HSCs) and human renal proximal tubular epithelial cells (HRPTEpiCs) Basic Protocol 2: Expansion of primary human lung fibroblasts (HLFs) Alternate Protocol 1: Isolation and expansion of primary mouse lung fibrob
Aguib Y, Allouba M, Walsh R, et al., 2021, New variant with a previously unrecognized mechanism of pathogenicity in hypertrophic cardiomyopathy, Circulation, Vol: 144, Pages: 754-757, ISSN: 0009-7322
Patel PN, Ito K, Willcox JAL, et al., 2021, Contribution of noncanonical splice variants to TTN truncating variants cardiomyopathy, Circulation: Genomic and Precision Medicine, Vol: 14, Pages: 1-10, ISSN: 2574-8300
Background:Heterozygous TTN truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as TTN truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain.Methods:Rare variants of unknown significance located in the splice regions of highly expressed TTN exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay.Results:Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (P=0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in TTN splice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site (P=4.4×107) and position -3 of the acceptor site (P=0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%–95%) but poor sensitivity (15%–50%) for the detection of splice-altering variants. Alternate exons spliced out of most TTN transcripts frequently lacked the consensus base at +5 donor and −3 acceptor positions.Conclusions:Noncanonical splice-altering variants in TTN explain 1-2% of DCM and offer a 10-20% increase in the diagnostic power of TTN sequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternate TTN exons.
Ng B, Widjaja AA, Viswanathan S, et al., 2021, Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis, Scientific Reports, Vol: 11, Pages: 1-12, ISSN: 2045-2322
Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11−/−) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11−/− mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11−/− mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11−/− female mice are infertile. Unlike Il11ra1−/− mice, Il11−/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.
Bylstra Y, Lim WK, Kam S, et al., 2021, Correction to: Family history assessment significantly enhances delivery of precision medicine in the genomics era., Genome Medicine: medicine in the post-genomic era, Vol: 13, Pages: 1-1, ISSN: 1756-994X
Widjaja AA, Dong J, Adami E, et al., 2021, Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury, SCIENCE TRANSLATIONAL MEDICINE, Vol: 13, ISSN: 1946-6234
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Wright CF, Quaife NM, Ramos-Hernández L, et al., 2021, Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms, American Journal of Human Genetics, Vol: 108, Pages: 1083-1094, ISSN: 0002-9297
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
Le T-T, Lim V, Ibrahim R, et al., 2021, The remodelling index risk stratifies patients with hypertensive left ventricular hypertrophy, European Heart Journal - Cardiovascular Imaging, Vol: 22, Pages: 670-679, ISSN: 2047-2404
AIMS: Hypertensive left ventricular hypertrophy (LVH) is associated with increased cardiovascular events. We previously developed the remodelling index (RI) that incorporated left ventricular (LV) volume and wall-thickness in a single measure of advanced hypertrophy in hypertensive patients. This study examined the prognostic potential of the RI in reference to contemporary LVH classifications. METHODS AND RESULTS: Cardiovascular magnetic resonance was performed in 400 asymptomatic hypertensive patients. The newly derived RI (EDV3t, where EDV is LV end-diastolic volume and t is the maximal wall thickness across 16 myocardial segments) stratified hypertensive patients: no LVH, LVH with normal RI (LVHNormal-RI), and LVH with low RI (LVHLow-RI). The primary outcome was a composite of all-cause mortality, acute coronary syndromes, strokes, and decompensated heart failure. LVHLow-RI was associated with increased LV mass index, fibrosis burden, impaired myocardial function and elevated biochemical markers of myocardial injury (high-sensitive cardiac troponin I), and wall stress. Over 18.3 ± 7.0 months (601.3 patient-years), 14 adverse events occurred (2.2 events/100 patient-years). Patients with LVHLow-RI had more than a five-fold increase in adverse events compared to those with LVHNormal-RI (11.6 events/100 patient-years vs. 2.0 events/100 patient-years, respectively; log-rank P < 0.001). The RI provided incremental prognostic value over and above a model consisting of clinical variables, LVH and concentricity; and predicted adverse events independent of clinical variables, LVH, and other prognostic markers. Concentric and eccentric LVH were associated with adverse prognosis (log-rank P = 0.62) that was similar to the natural history of hypertensive LVH (5.1 events/100 patient-years). CONCLUSION: The RI provides prognostic value that improves risk stratification of hypertensive LVH.
Tayal U, Verdonschot J, Hazebroek M, et al., 2021, MULTI-PARAMETRIC PHENOMAPPING USING MACHINE LEARNING IDENTIFIES A NOVEL SUBTYPE OF DILATED CARDIOMYOPATHY AND HIGHLIGHTS IL4R AS A NOVEL PROGNOSTIC BIOMARKER, 70th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 3408-3408, ISSN: 0735-1097
Lim W-W, Corden B, Ye L, et al., 2021, Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload, CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Vol: 48, Pages: 605-613, ISSN: 0305-1870
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Corden B, Lim W-W, Song W, et al., 2021, Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 14, Pages: 222-228, ISSN: 1937-5387
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- Citations: 10
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