Publications by authors named "Stuart A Cook"

167 Publications

Prognostic Significance of Nonischaemic Myocardial Fibrosis in Patients With Normal Left Ventricular Volumes and Ejection-Fraction.

JACC Cardiovasc Imaging 2021 Jul 7. Epub 2021 Jul 7.

Cardiovascular Research Centre & Cardiovascular Magnetic Resonance Unit, Royal Brompton and Harefield Hospitals NHS Foundation Trust, London, United Kingdom; National Heart & Lung Institute, Imperial College London, London, United Kingdom.

Objectives: This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction.

Background: Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain.

Methods: Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD).

Results: Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38 years-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 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 (hazard ratio: 2.04 per 10 years; 95% confidence interval: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (hazard ratio: 7.22; 95% confidence interval: 4.26-21.17; P < 0.0001).

Conclusions: 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 cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia.
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http://dx.doi.org/10.1016/j.jcmg.2021.05.016DOI Listing
July 2021

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis.

Sci Rep 2021 Jul 8;11(1):14088. Epub 2021 Jul 8.

Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.

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.
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http://dx.doi.org/10.1038/s41598-021-93623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266813PMC
July 2021

Loss of Yap/taz in cardiac fibroblasts attenuates adverse remodeling and improves cardiac function.

Cardiovasc Res 2021 Jun 16. Epub 2021 Jun 16.

Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore. Singapore.

Aims: Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodeling 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 signaling 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 Results: Using 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 remodeling. 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 program 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 signaling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response.

Conclusions: We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program.

Translational Perspective: Cardiac fibroblasts are the most prevalent cell type in the heart and play an important role in regulating post-myocardial infarction (MI) cardiac fibrosis. Excessive cardiac fibrosis causes ventricular stiffness leading to systolic/diastolic cardiac dysfunction and heart failure. Therefore, understanding the molecular mechanism of cardiac fibroblasts activation will help to modulate the post-MI fibrotic response and improve cardiac function. In our study, we show that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program.
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http://dx.doi.org/10.1093/cvr/cvab205DOI Listing
June 2021

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Sci Transl Med 2021 06;13(597)

Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.

Acetaminophen (-acetyl--aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of () in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of were also protected from AILI, and deletion of or was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.
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http://dx.doi.org/10.1126/scitranslmed.aba8146DOI Listing
June 2021

Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.

Am J Hum Genet 2021 06 21;108(6):1083-1094. Epub 2021 May 21.

Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1RQ, UK; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

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.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206381PMC
June 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

Multiparametric exercise stress cardiovascular magnetic resonance in the diagnosis of coronary artery disease: the EMPIRE trial.

J Cardiovasc Magn Reson 2021 03 4;23(1):17. Epub 2021 Mar 4.

National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore.

Background: Stress cardiovascular magnetic resonance (CMR) offers assessment of ventricular function, myocardial perfusion and viability in a single examination to detect coronary artery disease (CAD). We developed an in-scanner exercise stress CMR (ExCMR) protocol using supine cycle ergometer and aimed to examine the diagnostic value of a multiparametric approach in patients with suspected CAD, compared with invasive fractional flow reserve (FFR) as the reference gold standard.

Methods: In this single-centre prospective study, patients who had symptoms of angina and at least one cardiovascular disease risk factor underwent both ExCMR and invasive angiography with FFR. Rest-based left ventricular function (ejection fraction, regional wall motion abnormalities), tissue characteristics and exercise stress-derived (perfusion defects, inducible regional wall motion abnormalities and peak exercise cardiac index percentile-rank) CMR parameters were evaluated in the study.

Results: In the 60 recruited patients with intermediate CAD risk, 50% had haemodynamically significant CAD based on FFR. Of all the CMR parameters assessed, the late gadolinium enhancement, stress-inducible regional wall motion abnormalities, perfusion defects and peak exercise cardiac index percentile-rank were independently associated with FFR-positive CAD. Indeed, this multiparametric approach offered the highest incremental diagnostic value compared to a clinical risk model (χ for the diagnosis of FFR-positive increased from 7.6 to 55.9; P < 0.001) and excellent performance [c-statistic area under the curve 0.97 (95% CI: 0.94-1.00)] in discriminating between FFR-normal and FFR-positive patients.

Conclusion: The study demonstrates the clinical potential of using in-scanner multiparametric ExCMR to accurately diagnose CAD.

Trial Registration: ClinicalTrials.gov, NCT03217227, Registered 11 July 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03217227?id=NCT03217227&draw=2&rank=1&load=cart.
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http://dx.doi.org/10.1186/s12968-021-00705-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931509PMC
March 2021

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling underlies TGFβ-mediated activation of dermal fibroblasts.

Rheumatology (Oxford) 2021 Feb 16. Epub 2021 Feb 16.

Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.

Objectives: Interleukin 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.

Methods: We 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.

Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11RA and the 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 signaling 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 pharmacologic inhibition of ERK.

Conclusions: These 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.
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http://dx.doi.org/10.1093/rheumatology/keab168DOI Listing
February 2021

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

Genet Med 2021 05 26;23(5):856-864. Epub 2021 Jan 26.

Amsterdam UMC, University of Amsterdam, Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam, Netherlands.

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.

Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).

Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.

Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.
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http://dx.doi.org/10.1038/s41436-020-01049-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105165PMC
May 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259PMC
February 2021

Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload.

Clin Exp Pharmacol Physiol 2021 04 18;48(4):605-613. Epub 2021 Jan 18.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.

Interleukin-11 (IL11) is important for fibroblast-to-myofibroblast transformations. Here, we examined the signalling and phenotypic effects of inhibiting IL11 signalling using neutralizing antibodies against IL11 or its cognate receptor (IL11RA) in a mouse model of acute and severe pressure overload. C57BL/6J mice underwent ascending aortic constriction (AAC) surgery and were randomized to anti-IL11, anti-IL11RA, or isotype control antibodies (20 mg/kg, bi-weekly for 2 weeks). AAC surgery induced the expression of IL11, IL11RA and extracellular matrix (ECM) genes that was associated with cardiac hypertrophy and aortic remodelling. Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy. STAT3 was phosphorylated in the hearts of AAC-treated mice but this was unrelated to IL11 activity, which we confirmed in mouse cardiac fibroblasts in vitro. These data highlight that blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway.
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http://dx.doi.org/10.1111/1440-1681.13458DOI Listing
April 2021

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH.

Nat Commun 2021 01 4;12(1):66. Epub 2021 Jan 4.

Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.
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http://dx.doi.org/10.1038/s41467-020-20303-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782504PMC
January 2021

Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway.

Exp Mol Med 2020 12 1;52(12):1871-1878. Epub 2020 Dec 1.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.
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http://dx.doi.org/10.1038/s12276-020-00531-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705429PMC
December 2020

The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: defining a healthy volunteer cohort.

NPJ Genom Med 2020 23;5:46. Epub 2020 Oct 23.

Aswan Heart Centre, Aswan, Egypt.

The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities toward advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations, such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1000 individuals free of cardiovascular disease (CVD). Here, we present the first 391 Egyptian healthy volunteers recruited to establish a pilot phenotyped control cohort. All individuals underwent detailed clinical investigation, including cardiac magnetic resonance imaging (MRI), and were sequenced using a targeted panel of 174 genes with reported roles in inherited cardiac conditions. We identified 1262 variants in 27 cardiomyopathy genes of which 15.1% were not captured in current global and regional genetic reference databases (here: gnomAD and Great Middle Eastern Variome). The ECCO-GEN project aims at defining the genetic landscape of an understudied population and providing individual-level genetic and phenotypic data to support future studies in CVD and population genetics.
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http://dx.doi.org/10.1038/s41525-020-00153-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584615PMC
October 2020

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models.

Sci Rep 2020 10 20;10(1):17853. Epub 2020 Oct 20.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore.

Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.
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http://dx.doi.org/10.1038/s41598-020-74944-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576123PMC
October 2020

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions.

Genet Med 2021 01 13;23(1):69-79. Epub 2020 Oct 13.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene-disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance.

Methods: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost's ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes.

Results: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4-24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11-29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy.

Conclusions: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions ( https://www.cardiodb.org/cardioboost/ ), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.
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http://dx.doi.org/10.1038/s41436-020-00972-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790749PMC
January 2021

Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

EMBO Mol Med 2020 10 21;12(10):e10865. Epub 2020 Sep 21.

MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK.

Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix-secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master-regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.
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http://dx.doi.org/10.15252/emmm.201910865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539225PMC
October 2020

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in and That Are Common in Chinese Patients.

Circ Genom Precis Med 2020 10 20;13(5):424-434. Epub 2020 Aug 20.

Cardiovascular Research Center, Royal Brompton Hospital, London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.).

Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.

Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.

Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, <0.0001) but an excess of variants of uncertain significance (24%, <0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, =0.0057, genome aggregation database-East Asian AF=0.0062, =0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, <0.0001, genome aggregation database-East Asian AF=0.0009, <0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83-0.97]) support the likely pathogenicity of TNNT2:p.R286H.

Conclusions: As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in or but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.
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http://dx.doi.org/10.1161/CIRCGEN.119.002823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676617PMC
October 2020

Genetic and functional insights into the fractal structure of the heart.

Nature 2020 08 19;584(7822):589-594. Epub 2020 Aug 19.

MRC London Institute of Medical Sciences, Imperial College London, London, UK.

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.
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http://dx.doi.org/10.1038/s41586-020-2635-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116759PMC
August 2020

Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease.

FASEB J 2020 09 12;34(9):11802-11815. Epub 2020 Jul 12.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.

Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Interleukin 11 (IL11) is important for pulmonary fibroblast activation but the contribution of fibroblast-specific IL11 activity to lung fibro-inflammation is not known. To address this gap in knowledge, we generated mice with loxP-flanked Il11ra1 and deleted the IL11 receptor in adult fibroblasts (CKO mice). In the bleomycin (BLM) model of lung fibrosis, CKO mice had reduced fibrosis, lesser fibroblast ERK activation, and diminished immune cell STAT3 phosphorylation. Following BLM injury, acute inflammation in CKO mice was similar to controls but chronic immune infiltrates and pro-inflammatory gene activation, including NF-kB phosphorylation, were notably reduced. Therapeutic prevention of IL11 activity with neutralizing antibodies mirrored the effects of genetic deletion of Il11ra1 in fibroblasts. These data reveal a new function for IL11 in pro-inflammatory lung fibroblasts and highlight the important contribution of the stroma to inflammation in pulmonary disease.
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http://dx.doi.org/10.1096/fj.202001045RRDOI Listing
September 2020

Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice.

J Cardiovasc Transl Res 2021 Apr 26;14(2):222-228. Epub 2020 Jun 26.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.

There are currently no specific treatments for cardiac fibrosis. We tested the efficacy of a neutralising anti-IL11 antibody (X203) to reduce cardiac fibrosis in two preclinical models: transverse aortic constriction (TAC) and chronic angiotensin II infusion (AngII). In the first model, male C57BL/6J mice were subjected to TAC for 2 weeks. In the second model, mice received continuous angiotensin II for 4 weeks via subcutaneous pump. In both models, mice received either 20 mg/kg of X203 or isotype-control antibody twice-weekly, starting 24 h after surgery. Cardiac fibrosis and extracellular matrix gene expression were assessed by RT-qPCR, Western blot, histology and collagen (hydroxyproline) assays. In both models, X203 significantly reduced pro-fibrotic gene expression and myocardial fibrosis (TAC: 51% reduction in total collagen, P < 0.001, 39% in perivascular fibrosis, P < 0.001; AngII: 17% reduction in total collagen, P = 0.04, 83% in perivascular fibrosis, P < 0.001). Pharmacological targeting of IL11 reduces cardiac fibrosis in preclinical models. Figa Graphical Abstract.
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http://dx.doi.org/10.1007/s12265-020-10054-zDOI Listing
April 2021

Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy.

Hum Vaccin Immunother 2020 10 12;16(10):2357-2362. Epub 2020 Jun 12.

Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School , Singapore.

The interleukin 6 (IL6) family of proteins regulate important cellular processes and act through a variety of signaling pathways via a shared gp130 receptor. In the liver, there is a large body of evidence showing a protective and pro-regenerative role for IL6 and signaling. While a few studies suggest a pathological role for IL6 -signaling in the liver. IL11 is often thought of as similar to IL6 and redundancy has been inferred. However, recent studies reveal that IL6R and IL11RA are expressed on dissimilar cell types and these cytokines actually have very different roles in biology and pathology. In the liver, IL6R is mostly expressed on immune cells, whereas IL11RA is highly expressed on hepatocytes and hepatic stellate cells, both of which exhibit autocrine IL11 activity. In contrast to the beneficial effects of IL6 in the liver, IL11 causes liver disease and its expression in stromal and parenchymal cells leads to fibrosis, inflammation, steatosis and hepatic failure. In this review, we address IL6 and IL11 in the context of liver function. We end by discussing the possibility of IL6 gain-of-function versus IL11 inhibition as therapeutic approaches to treat liver disease. .
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http://dx.doi.org/10.1080/21645515.2020.1761203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644218PMC
October 2020

Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals.

Nat Commun 2020 05 27;11(1):2523. Epub 2020 May 27.

National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, Du Cane Road, London, W12 0NN, UK.

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.
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http://dx.doi.org/10.1038/s41467-019-10717-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253449PMC
May 2020

Evaluation of family health history collection methods impact on data and risk assessment outcomes.

Prev Med Rep 2020 Jun 5;18:101072. Epub 2020 Mar 5.

SingHealth Duke-NUS Institute of Precision Medicine, Duke-National University of Singapore Medical School, Singapore.

Information technology applications for patient-collection of family health history (FHH) increase identification of elevated-risk individuals compared to usual care. It is unknown if the method of collection impacts data collected or if simply going directly to the patient is what makes the difference. The objective of this study was to examine differences in data detail and risk identification rates between FHH collection directly from individuals using paper-based forms and an interactive web-based platform. This is a non-randomized epidemiologic study in Singaporean population from 2016 to 2018. Intervention was paper-based versus web-based interactive platform for FHH collection. Participant demographics, FHH detail, and risk assessment results were analyzed. 882 participants enrolled in the study, 481 in the paper-based group and 401 in the web-based group with mean (SD) age of 45.4 (12.98) years and 47.5% male. Web-based FHH collection participants had an increased number of conditions per relative (p-value <0.001), greater frequency of reporting age of onset (p-value <0.001), and greater odds of receiving ≥1 risk recommendation both overall (OR: 3.99 (2.41, 6.59)) and within subcategories of genetic counselling for hereditary cancer syndromes (p-value = 0.041) and screening and prevention for breast (p-value = 0.002) and colon cancer (p-value = 0.005). This has significant implications for clinical care and research efforts where FHH is being assessed. Using interactive information technology platforms to collect FHH can improve the completeness of the data collected and result in increased rates of risk identification. Methods of data collection to maximize benefit should be taken into account in future studies and clinical care.
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http://dx.doi.org/10.1016/j.pmedr.2020.101072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066218PMC
June 2020

Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 03;75(10):1196-1207

Department of Cardiovascular Sciences, University of Leicester and the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. Electronic address:

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.
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http://dx.doi.org/10.1016/j.jacc.2019.12.058DOI Listing
March 2020

Paradoxical Higher Myocardial Wall Stress and Increased Cardiac Remodeling Despite Lower Mass in Females.

J Am Heart Assoc 2020 02 12;9(4):e014781. Epub 2020 Feb 12.

National Heart Research Institute Singapore National Heart Center Singapore Singapore.

Background Increased left ventricular (LV) mass is characterized by increased myocardial wall thickness and/or ventricular dilatation that is associated with worse outcomes. We aim to comprehensively compare sex-stratified associations between measures of LV remodeling and increasing LV mass in the general population. Methods and Results Participants were prospectively recruited in the National Heart Center Singapore Biobank to examine health and cardiovascular risk factors in the general population. Cardiovascular magnetic resonance was performed in all individuals. Participants with established cardiovascular diseases and abnormal cardiovascular magnetic resonance scan results were excluded. Global and regional measures of LV remodeling (geometry, function, interstitial volumes, and wall stress) were performed using conventional image analysis and novel 3-dimensional machine learning phenotyping. Sex-stratified analyses were performed in 1005 participants (57% males; 53±13 years). Age and prevalence of cardiovascular risk factors were well-matched in both sexes (>0.05 for all). Progressive increase in LV mass was associated with increased concentricity in either sex, but to a greater extent in females. Compared with males, females had higher wall stress (mean difference: 170 mm Hg, <0.0001) despite smaller LV mass (42.4±8.2 versus 55.6±14.2 g/m, <0.0001), lower blood pressures (<0.0001), and higher LV ejection fraction (61.9±5.9% versus 58.6±6.4%, <0.0001). The regions of increased concentric remodeling corresponded to regions of increased wall stress. Compared with males, females had increased extracellular volume fraction (27.1±2.4% versus 25.1±2.9%, <0.0001). Conclusions Compared with males, females have lower LV mass, increased wall stress, and concentric remodeling. These findings provide mechanistic insights that females are susceptible to particular cardiovascular complications.
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http://dx.doi.org/10.1161/JAHA.119.014781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070215PMC
February 2020

Predictors of left ventricular remodelling in patients with dilated cardiomyopathy - a cardiovascular magnetic resonance study.

Eur J Heart Fail 2020 07 13;22(7):1160-1170. Epub 2020 Feb 13.

National Heart Lung Institute, Imperial College London, UK.

Aims: There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.

Methods And Results: Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = -0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease-modifying heart failure medication (beta-blocker, P = 0.28; angiotensin-converting enzyme inhibitor, P = 0.92) did not predict follow-up LVEF.

Conclusions: Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.
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http://dx.doi.org/10.1002/ejhf.1734DOI Listing
July 2020

IL-11 in cardiac and renal fibrosis: Late to the party but a central player.

Br J Pharmacol 2020 04 22;177(8):1695-1708. Epub 2020 Feb 22.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.

Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in the kidney, it is the final common pathway for many diseases and predicts end-stage renal failure. Despite this, there are currently no specific anti-fibrotic treatments available for cardiac or renal disease. Recently and unexpectedly, IL-11 was found to be of major importance for cardiorenal fibroblast activation and fibrosis. In mouse models, IL-11 overexpression caused fibrosis of the heart and kidney while genetic deletion of Il11ra1 protected against fibrosis and preserved organ function. Neutralizing antibodies against IL-11 or IL-11RA have been developed that have anti-fibrotic activity in human fibroblasts and protect against fibrosis in murine models of disease. While IL-11 biology has been little studied and, we suggest, largely misunderstood, its autocrine activity in myofibroblasts appears non-redundant for fibrosis, which offers new opportunities to better understand and potentially target cardiorenal fibrosis.
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http://dx.doi.org/10.1111/bph.15013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070163PMC
April 2020
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