DONA ORA
Pubblicazioni recenti - cardiac fibrosis
-
Downregulation of microRNA-21-5p from macrophages-derived exosomes represses ventricular remodeling after myocardial infarction via inhibiting tissue inhibitors of metalloproteinase 3.
Int Immunopharmacol2021 Apr;96():107611. doi: S1567-5769(21)00247-2.
Dong Jing, Zhu Wanjie, Wan Daguo,
Abstract
OBJECTIVE:
Exosomes are known to transfer microRNAs (miRNAs) to affect the progression of human diseases. We aim to explore the role of M1 macrophages-derived exosomes (M1 exosomes) conveying miR-21-5p in ventricular remodeling in mice with myocardial infarction (MI) by regulating tissue inhibitors of metalloproteinase 3 (TIMP3).
METHODS:
Macrophages were isolated and co-cultured with miR-21-5p antagomir to extract the exosomes. The modeled mice were injected with relative exosomes to investigate their roles in the cardiac function, pathology of myocardial tissue, myocardial fibrosis, cardiomyocyte apoptosis and ventricular remodeling in MI mice. The expression of miR-21-5p and TIMP3 was detected and their targeting relationship was analyzed.
RESULTS:
MiR-21-5p was upregulated while TIMP3 was downregulated in MI mouse myocardial tissues. M1 exosomes impaired cardiac function, aggravated pathology of myocardial tissue, myocardial fibrosis and ventricular remodeling, and promoted cardiomyocyte apoptosis in MI mice. M1 exosomes containing miR-21-5p antagomir alleviated the above alterations, while the role of exosomes containing miR-21-5p antagomir was reversed by silencing TIMP3. TIMP3 was targeted by miR-21-5p.
CONCLUSION:
Downregulation of miR-21-5p from macrophages-derived exosomes suppresses ventricular remodeling after MI via inhibiting TIMP3.
Copyright © 2021 Elsevier B.V. All rights reserved.
Guarda su PubMed
-
Histopathological Features of Fibrous Cephalic Plaques in Tuberous Sclerosis Complex.
Histopathology2021 Apr;():. doi: 10.1111/his.14392.
Treichel Alison M, Pithadia Deeti J, Lee Chyi-Chia R, Oyerinde Oyetewa, Moss Joel, Darling Thomas N,
Abstract
BACKGROUND:
Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis.
AIM:
To determine the range of histopathological features of FCPs.
METHODS:
A retrospective analysis was conducted on 119 adults with TSC. Twenty-one lesions from 16 individuals were evaluated by a dermatopathologist. Additionally, we assessed if lesion color or histology varied by anatomical location.
RESULTS:
Seventy-six lesions were observed in 36/119 individuals. Erythematous lesions were more commonly found on the forehead, face, or neck than the scalp (OR=12.6, p=0.0001). Thickened and disorganized collagen fiber bundles were present in 95% (20/21). Perifollicular fibrosis was observed in 95% (20/21), enhanced vascularity in 52% (11/21), and features of fibrofolliculoma in 43% (9/21) of lesions. Other abnormalities included features similar to trichofolliculoma, follicular-derived, infundibular-type cysts, and abnormally arranged primitive hair follicles.
CONCLUSIONS:
FCPs in TSC exhibit thickened bundles of collagen and hamartomatous changes involving hair follicles. Recognition of these histopathological features may raise the possibility of unsuspected TSC or confirm FCP identification.
This article is protected by copyright. All rights reserved.
Guarda su PubMed
-
The evolution of computer-based analysis of high-resolution CT of the chest in patients with IPF.
Br J Radiol2021 Apr;():20200944. doi: 10.1259/bjr.20200944.
Calandriello Lucio, Walsh Simon Lf,
Abstract
In patients with idiopathic pulmonary fibrosis (IPF), there is an urgent need of biomarkers which can predict disease behaviour or response to treatment. Most published studies report results based on continuous data which can be difficult to apply to individual patients in clinical practice. Having antifibrotic therapies makes it even more important that we can accurately diagnose and prognosticate in IPF patients. Advances in computer technology over the past decade have provided computer-based methods for objectively quantifying fibrotic lung disease on high-resolution CT of the chest with greater strength than visual CT analysis scores. These computer-based methods and, more recently, the arrival of deep learning-based image analysis might provide a response to these unsolved problems. The purpose of this commentary is to provide insights into the problems associated with visual interpretation of HRCT, describe of the current technologies used to provide quantification of disease on HRCT and prognostication in IPF patients, discuss challenges to the implementation of this technology and future directions.
Guarda su PubMed
-
Emerging role of non-coding RNA in health and disease.
Metab Brain Dis2021 Apr;():. doi: 10.1007/s11011-021-00739-y.
Bhatti Gurjit Kaur, Khullar Naina, Sidhu Inderpal Singh, Navik Uma Shanker, Reddy Arubala P, Reddy P Hemachandra, Bhatti Jasvinder Singh,
Abstract
Human diseases have always been a significant turf of concern since the origin of mankind. It is cardinal to know the cause, treatment, and cure for every disease condition. With the advent and advancement in technology, the molecular arena at the microscopic level to study the mechanism, progression, and therapy is more rational and authentic pave than a macroscopic approach. Non-coding RNAs (ncRNAs) have now emerged as indispensable players in the diagnosis, development, and therapeutics of every abnormality concerning physiology, pathology, genetics, epigenetics, oncology, and developmental diseases. This is a comprehensive attempt to collate all the existing and proven strategies, techniques, mechanisms of genetic disorders including Silver Russell Syndrome, Fascio- scapula humeral muscular dystrophy, cardiovascular diseases (atherosclerosis, cardiac fibrosis, hypertension, etc.), neurodegenerative diseases (Spino-cerebral ataxia type 7, Spino-cerebral ataxia type 8, Spinal muscular atrophy, Opitz-Kaveggia syndrome, etc.) cancers (cervix, breast, lung cancer, etc.), and infectious diseases (viral) studied so far. This article encompasses discovery, biogenesis, classification, and evolutionary prospects of the existence of this junk RNA along with the integrated networks involving chromatin remodelling, dosage compensation, genome imprinting, splicing regulation, post-translational regulation and proteomics. In conclusion, all the major human diseases are discussed with a facilitated technology transfer, advancements, loopholes, and tentative future research prospects have also been proposed.
Guarda su PubMed
-
Adipose-Derived Mesenchymal Stem Cells-Derived Exosomes Carry MicroRNA-671 to Alleviate Myocardial Infarction Through Inactivating the TGFBR2/Smad2 Axis.
Inflammation2021 Apr;():. doi: 10.1007/s10753-021-01460-9.
Wang Xue, Zhu Yuhai, Wu Chengcheng, Liu Wennan, He Yujie, Yang Qing,
Abstract
Mesenchymal stem cells (MSCs) and their derived extracellular vesicles have been reported as promising tools for the management of heart disease. The aim of this study was to explore the function of adipose-derived MSCs (adMSCs)-derived exosomes (Exo) in the progression of myocardial infarction (MI) and the molecules involved. Mouse cardiomyocytes were treated with oxygen-glucose deprivation (OGD) to mimic an MI condition in vitro. The adMSCs-derived Exo were identified and administrated into the OGD-treated cardiomyocytes, and then the viability and apoptosis of cells, and the secretion of fibrosis- and inflammation-related cytokines in cells were determined. Differentially expressed microRNAs (miRNAs) in cells after Exo treatment were screened using a microarray analysis. The downstream molecules regulated by miR-671 were explored through bioinformatic analysis. Involvements of miR-671 and transforming growth factor beta receptor 2 (TGFBR2) in the exosome-mediated events were confirmed by rescue experiments. A murine model with MI was induced and treated with Exo for functional experiments in vivo. Compared to phosphate-buffered saline treatment, the Exo treatment significantly enhanced viability while reduced apoptosis of cardiomyocytes, and in reduced myocardial fibrosis and inflammation both in vitro and in vivo. miR-671 was significantly upregulated in cells after Exo treatment. Downregulation of miR-671 blocked the protective functions of Exo. miR-671 targeted TGFBR2 and suppressed phosphorylation of Smad2. Artificial downregulation of TGFBR2 enhanced viability of the OGD-treated cardiomyocytes. This study suggested that adMSC-derived exosomal miR-671 directly targets TGFBR2 and reduces Smad2 phosphorylation to alleviate MI-like symptoms both in vivo and in vitro.
Guarda su PubMed
-
Integrating Measures of Myocardial Fibrosis in the Transition from Hypertensive Heart Disease to Heart Failure.
Curr Hypertens Rep2021 Apr;23(4):22. doi: 10.1007/s11906-021-01135-8.
Stacey R Brandon, Hundley W Gregory,
Abstract
PURPOSE OF REVIEW:
This review aims to summarize recent developments in identifying and quantifying both the presence and amount of myocardial fibrosis by imaging and biomarkers. Further, this review seeks to describe in general ways how this information may be used to identify hypertension and the transition to heart failure with preserved ejection fraction.
RECENT FINDINGS:
Recent studies using cardiac magnetic resonance imaging highlight the progressive nature of fibrosis from normal individuals to those with hypertension to those with clinical heart failure. However, separating hypertensive patients from those with heart failure remains challenging. Recent studies involving echocardiography show the subclinical myocardial strain changes between hypertensive heart disease and heart failure. Lastly, recent studies highlight the potential use of biomarkers to identify those with hypertension at the greatest risk of developing heart failure. In light of the heterogeneous nature between hypertension and heart failure with preserved ejection fraction, an integrated approach with cardiac imaging and biomarker analysis may enable clinicians and investigators to more accurately characterize, prevent, and treat heart failure in those with hypertension.
Guarda su PubMed
-
Role of oxidative stress in calcific aortic valve disease and its therapeutic implications.
Cardiovasc Res2021 Apr;():. doi: cvab142.
Greenberg Harry Z E, Zhao Guoan, Shah Ajay M, Zhang Min,
Abstract
Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
Guarda su PubMed
-
Urinary peptides in heart failure: a link to molecular pathophysiology.
Eur J Heart Fail2021 Apr;():. doi: 10.1002/ejhf.2195.
He Tianlin, Mischak Michaela, Clark Andrew L, Campbell Ross T, Delles Christian, Díez Javier, Filipatos Gerasimos, Mebazaa Alexandre, McMurray John J V, González Arantxa, Raad Julia, Stroggilos Rafael, Bosselmann Helle S, Campbell Archie, Kerr Shona, Jackson Colette E, Cannon Jane A, Schou Morten, Girerd Nicolas, Rossignol Patrick, McConnachie Alex, Rossing Kasper, Schanstra Joost P, Zannad Faiez, Vlahou Antonia, Mullen William, Jankowski Vera, Mischak Harald, Zhang Zhenyu, Staessen Jan A, Latosinska Agnieszka,
Abstract
AIMS:
Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology.
METHODS AND RESULTS:
Analysable data from 5,608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (p<0.0001). No separation based on HF subtype was detectable.
CONCLUSIONS:
HF, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.
This article is protected by copyright. All rights reserved.
Guarda su PubMed
-
Pneumoconiosis: current status and future prospects.
Chin Med J (Engl)2021 Apr;134(8):898-907. doi: 10.1097/CM9.0000000000001461.
Qi Xian-Mei, Luo Ya, Song Mei-Yue, Liu Ying, Shu Ting, Liu Ying, Pang Jun-Ling, Wang Jing, Wang Chen,
Abstract
ABSTRACT:
Pneumoconiosis refers to a spectrum of pulmonary diseases caused by inhalation of mineral dust, usually as the result of certain occupations. The main pathological features include chronic pulmonary inflammation and progressive pulmonary fibrosis, which can eventually lead to death caused by respiratory and/or heart failure. Pneumoconiosis is widespread globally, seriously threatening global public health. Its high incidence and mortality lie in improper occupational protection, and in the lack of early diagnostic methods and effective treatments. This article reviews the epidemiology, safeguard procedures, diagnosis, and treatment of pneumoconiosis, and summarizes recent research advances and future research prospects.
Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
Guarda su PubMed
-
.
J Pharmacol Exp Ther2021 Apr;():. doi: JPET-AR-2020-000424.
Kuppuswamy Dhandapani, Chinnakkannu Panneerselvam, Reese Charles, Hoffman Stanley,
Abstract
Aging is a progressive, multifactorial degenerative process in which deleterious changes occur in the biochemistry and function of organs. We showed that angiotensin II (AngII)-induced pathologies in the heart and kidney of young, 3-month-old mice are suppressed by the caveolin-1 scaffolding domain (CSD) peptide. Because AngII mediates many aging-associated changes, we explored whether CSD could reverse preexisting pathologies and improve organ function in aged mice. Using 18-month-old mice (similar to 60-year-old humans), we found that >5-fold increases in leakage of serum proteins and >2-fold increases in fibrosis are associated with aging in the heart, kidney, and brain. Because tyrosine phosphorylation of cell junction proteins leads to the loss of microvascular barrier function, we analyzed the activation of the receptor tyrosine kinase PDGFR and the non-receptor tyrosine kinases c-Src and Pyk2. We observed 5-fold activation of PDGFR and 2 to 3-fold activation of c-Src and Pyk2 in aged mice. Treatment with CSD for four weeks reversed these pathological changes (microvascular leakage, fibrosis, kinase activation) in all organs almost down to the levels in healthy, young mice. In studies of heart function, CSD reduced the aging-associated increase in cardiomyocyte cross-sectional area and enhanced ventricular compliance in that echocardiographic studies demonstrated improved ejection fraction and fractional shortening and reduced isovolumic relation time. These results suggest that versions of CSD may be developed as treatments for aging-associated diseases in human patients based on the concept that CSD inhibits tyrosine kinases leading to the inhibition of microvascular leakage and associated fibrosis, thereby improving organ function. The caveolin-1 scaffolding domain peptide (CSD) reverses aging-associated fibrosis, microvascular leakage, and organ dysfunction in the heart, kidneys, and brain via a mechanism that involves the suppression of the activity of multiple tyrosine kinases, suggesting that CSD can be developed as a treatment for a wide range of diseases found primarily in the aged.
Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics.
Guarda su PubMed
-
A nutraceutical strategy for downregulating TGF? signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis.
Open Heart2021 Apr;8(1):. doi: e001663.
DiNicolantonio James J, McCarty Mark F, Barroso-Aranda Jorge, Assanga Simon, Lujan Lidianys Maria Lewis, O'Keefe James H,
Guarda su PubMed
-
Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia.
Biol Sex Differ2021 Apr;12(1):31. doi: 10.1186/s13293-021-00376-1.
Richards Claire, Sesperez Kimberly, Chhor Michael, Ghorbanpour Sahar, Rennie Claire, Ming Clara Liu Chung, Evenhuis Chris, Nikolic Valentina, Orlic Natasa Karadzov, Mikovic Zeljko, Stefanovic Milan, Cakic Zoran, McGrath Kristine, Gentile Carmine, Bubb Kristen, McClements Lana,
Abstract
BACKGROUND:
Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia.
METHODS:
The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ? 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling.
RESULTS:
The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein expression (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06).
CONCLUSIONS:
The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.
Guarda su PubMed
-
Evaluating the prevalence and severity of NAFLD in primary care: the EPSONIP study protocol.
BMC Gastroenterol2021 Apr;21(1):180. doi: 10.1186/s12876-021-01763-z.
Nasr Patrik, Iredahl Fredrik, Dahlström Nils, Rådholm Karin, Henriksson Pontus, Cedersund Gunnar, Dahlqvist Leinhard Olof, Ebbers Tino, Alfredsson Joakim, Carlhäll Carl-Johan, Lundberg Peter, Kechagias Stergios, Ekstedt Mattias,
Abstract
BACKGROUND:
Non-alcoholic fatty liver disease (NAFLD) affects 20-30% of the general adult population. NAFLD patients with type 2 diabetes mellitus (T2DM) are at an increased risk of advanced fibrosis, which puts them at risk of cardiovascular complications, hepatocellular carcinoma, or liver failure. Liver biopsy is the gold standard for assessing hepatic fibrosis. However, its utility is inherently limited. Consequently, the prevalence and characteristics of T2DM patients with advanced fibrosis are unknown. Therefore, the purpose of the current study is to evaluate the prevalence and severity of NAFLD in patients with T2DM by recruiting participants from primary care, using the latest imaging modalities, to collect a cohort of well phenotyped patients.
METHODS:
We will prospectively recruit 400 patients with T2DM using biomarkers to assess their status. Specifically, we will evaluate liver fat content using magnetic resonance imaging (MRI); hepatic fibrosis using MR elastography and vibration-controlled transient elastography; muscle composition and body fat distribution using water-fat separated whole body MRI; and cardiac function, structure, and tissue characteristics, using cardiovascular MRI.
DISCUSSION:
We expect that the study will uncover potential mechanisms of advanced hepatic fibrosis in NAFLD and T2DM and equip the clinician with better diagnostic tools for the care of T2DM patients with NAFLD.
TRIAL REGISTRATION:
Clinicaltrials.gov, identifier NCT03864510. Registered 6 March 2019, https://clinicaltrials.gov/ct2/show/NCT03864510 .
Guarda su PubMed
-
Assessment of electrospun cardiac patches made with sacrificial particles and polyurethane-polycaprolactone blends.
J Biomed Mater Res A2021 Apr;():. doi: 10.1002/jbm.a.37201.
Beck Emily C, Jarrell Dillon K, Lyons Anne C, Vanderslice Ethan J, VeDepo Mitchell C, Jacot Jeffrey G,
Abstract
Congenital heart defects (CHDs) are the leading cause of death in live-born infants. Currently, patches used in the repair of CHDs are exclusively inert and non-degradable, which increases the risk of arrhythmia, follow-up surgeries, and sudden cardiac death. In this preliminary study, we sought to fabricate biodegradable scaffolds that can support cardiac regeneration in the repair of CHDs. We electrospun biodegradable scaffolds using various blends of polyurethane (PU) and polycaprolactone (PCL) with and without sacrificial poly(ethylene oxide) (PEO) particles and assessed the mechanical properties, cell infiltration levels, and inflammatory response in vitro (surface cell seeding) and in vivo (subcutaneous mouse implant). We hypothesized that a blend of the two polymers would preserve the low stiffness of PU as well as the high cell infiltration observed in PCL scaffolds. The inclusion of PU in the blends, even as low as 10%, decreased cell infiltration both in vitro and in vivo. The inclusion of sacrificial PEO increased pore sizes, reduced Young's moduli, and reduced the inflammatory response in all scaffold types. Collectively, we have concluded that a PCL patch electrospun with sacrificial PEO particles is the most promising scaffold for further assessment as in our heart defect model.
© 2021 Wiley Periodicals LLC.
Guarda su PubMed
-
Prevalence and prognostic impact of physical frailty in interstitial lung disease: A prospective cohort study.
Respirology2021 Apr;():. doi: 10.1111/resp.14066.
Farooqi Mohammed A Malik, O'Hoski Sachi, Goodwin Sarah, Makhdami Nima, Aziz Afia, Cox Gerard, Wald Joshua, Ryerson Christopher J, Beauchamp Marla K, Hambly Nathan, Kolb Martin,
Abstract
BACKGROUND AND OBJECTIVE:
Physical frailty is associated with increased mortality and hospitalizations in older adults. We describe the prevalence of physical frailty and its prognostic impact in patients with a spectrum of fibrotic interstitial lung disease (ILD).
METHODS:
Patients with fibrotic ILD at the McMaster University ILD programme were prospectively followed up from November 2015 to March 2020. Baseline data were used to classify patients as non-frail (score = 0), pre-frail (score = 1-2) or frail (score = 3-5) based on modified Fried physical frailty criteria. The association between physical frailty and mortality was assessed using time-to-event models, adjusted for age, sex, lung function and diagnosis using the ILD Gender-Age-Physiology (ILD-GAP) score.
RESULTS:
We included 463 patients (55% male, mean [SD] age 68 [11] years); 82 (18%) were non-frail, 258 (56%) pre-frail and 123 (26%) frail. The most common ILD diagnoses were idiopathic pulmonary fibrosis (n = 183, 40%) and connective tissue disease-associated-ILD (n = 79, 17%). Mean time since diagnosis was 2.7?±?4.6?years. There were 56 deaths within the median follow-up of 1.71 (interquartile range [IQR] 1.24, 2.31) years. Both frail and pre-frail individuals had a higher risk of death compared to those categorized as non-frail at baseline (adjusted hazard ratio [aHR] 4.14, 95% CI 1.27-13.5 for pre-frail and aHR 4.41, 95% CI 1.29-15.1 for frail).
CONCLUSION:
Physical frailty is prevalent in patients with ILD and is independently associated with an increased risk of death. Assessment of physical frailty provides additional prognostic value to recognized risk scores such as the ILD-GAP score, and may present a modifiable target for intervention.
© 2021 Asian Pacific Society of Respirology.
Guarda su PubMed
-
Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?
J Cyst Fibros2021 Apr;():. doi: S1569-1993(21)00109-0.
Dobra R, Davies G, Pike K, Strassle C, Allen L, Brendell R, Brownlee K, Carr S B, Simmonds N J, Davies J C, ,
Abstract
BACKGROUND:
Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes.
METHODS:
We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis.
RESULTS:
We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation.
CONCLUSIONS:
Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.
Copyright © 2021. Published by Elsevier B.V.
Guarda su PubMed
-
Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity.
Cardiooncology2021 Apr;7(1):15. doi: 10.1186/s40959-021-00100-3.
Hoffman Rebecca K, Kim Bang-Jin, Shah Payal D, Carver Joseph, Ky Bonnie, Ryeom Sandra,
Abstract
BACKGROUND:
Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC.
METHODS:
Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5?mg/kg) and trastuzumab (4?mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro.
RESULTS:
The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4?months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e'). Histological staining with Masson's trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells.
CONCLUSIONS:
An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.
Guarda su PubMed
-
Fibroblast-Specific Proteo-Transcriptomes Reveal Distinct Fibrotic Signatures of Human Sinoatrial Node in Non-Failing and Failing Hearts.
Circulation2021 Apr;():. doi: 10.1161/CIRCULATIONAHA.120.051583.
Kalyanasundaram Anuradha, Li Ning, Gardner Miranda L, Artiga Esthela J, Hansen Brian J, Webb Amy, Freitas Michael A, Pietrzak Maciej, Whitson Bryan A, Mokadam Nahush A, Janssen Paul M L, Mohler Peter J, Fedorov Vadim V,
Abstract
Up to fifty percent of the adult human sinoatrial node (SAN), is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may further increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atria. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment. Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted non-failing (non-HF, n=22; 48.7±3.1y.o,) and HF human hearts (n=16; 54.9±2.6y.o.). Connective tissue content was quantified from Masson's trichrome stained head-center and center-tail SAN sections. Expression of extracellular matrix (ECM) proteins, including Collagens 1, 3A1, cartilage intermediate layer protein 1 (CILP1) and periostin, fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (~10x5x2 mm) and right atria (RA) were isolated, cultured, passaged once, and treated ±transforming growth factor beta-1 (TGF?1) and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA and proteomic analyses. Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF vs non-HF hearts (57.7±2.6% vs 44.0±1.2% <0.0001). Proliferating phosphorylated histone3/vimentin/CD31 fibroblasts were higher in HF SAN. Vimentin/alpha smooth muscle actin/CD31 myofibroblasts along with increased interstitial periostin expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long non-coding RNA, microRNA and proteomic profiles between non-HF and HF SAN and RA fibroblasts, and TGF?1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with ECM flexibility, stiffness, focal adhesion and metabolism were altered in HF SAN fibroblasts compared to non-HF SAN. This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1 and periostin-positive interstitial fibrosis only in HF vs non-HF human hearts. Comprehensive proteo-transcriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN ECM in HF hearts. Fibroblast-specific profiles generated by our proteo-transcriptomic analyses of the human SAN, provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.
Guarda su PubMed
-
[Bilateral superior cervical ganglionectomy attenuates cardiac remodeling and improves cardiac function in pressure-overloaded heart failure mice].
Zhonghua Xin Xue Guan Bing Za Zhi2021 Apr;49(4):345-352. doi: 10.3760/cma.j.cn112148-20200603-00458.
Li G R, Li H, Lyu Z, Chen Z, Wang Y G,
Abstract
To investigate the effect of bilateral superior cervical ganglionectomy on cardiac remodeling and function in pressure-overloaded heart failure (HF) mice. Pressure-overloaded HF mouse model was produced by severe thoracic aorta banding (sTAB). Bilateral superior cervical ganglionectomy (SCGx) was performed 2 weeks after sTAB. Twenty four 6-week-old male C57BL/6 mice were randomized divided into 4 groups (=6 each): control group: sham sTAB+sham SCGx; denervated group: sham sTAB+SCGx; HF group: sTAB+sham SCGx; denervated HF group: sTAB+SCGx. Cardiac function was measured by echocardiography at week 0, 1, 2, and 4 after sTAB, respectively. All mice were sacrificed at the end of week 4 and heart tissues were harvested. HE and Masson staining were performed. Immunohistochemical staining (IHC) for tyrosine hydroxylase (TH), adrenergic receptor ?1 (AR-?1) and CD68 was performed. Western blot was used to determine the protein expression level of TH, B type natriuretic peptide (BNP), and AR-?1. Left ventricular ejection fraction (LVEF) declined continuously in HF group. LVEF was similar between denervated HF group and control group at various time points (>0.05). LVEF was significantly higher in denervated HF group than in HF group at the end of week 4 (<0.05). HE staining showed that cross sectional cardiomyocyte area was significantly larger in HF group than in control group and denervated HF group (<0.05), which was similar between denervated HF group and control group (>0.05). Masson staining showed that fibrosis level was significantly lower in denervated HF group than in HF group (<0.05). IHC showed that TH+nerves and CD68 macrophages were significantly increased in HF mice as compared to control mice (<0.05), whereas this change was abolished in denervated HF group. AR-?1 was significantly down-regulated in HF group compared with control group (<0.05), which was not affected by denervation (>0.05). Western blot demonstrated that the expression level of TH and BNP was significantly higher in HF group compared with the control group (<0.05), whereas this difference was diminished in denervated HF group(>0.05). Bilateral superior cervical ganglionectomy can reduce sympathetic innervation and macrophage infiltration in pressure overloaded failure heart, thus attenuate cardiac remodeling and improve cardiac function.
Guarda su PubMed
-
Getting to the heart of the matter: diagnostic tools and therapeutic approach to cardiac involvement in Behçet syndrome A Tunisian case series.
Reumatismo2021 Apr;73(1):32-43. doi: 10.4081/reumatismo.2021.1369.
Hammami A S, Jellazi M, Arfa S, Daada S, Ben Hamda K, Achour A, Ouali S,
Abstract
The aim was to investigate the frequency and spectrum of cardiac involvement (CI) in patients with Behçet syndrome (BS) in the Tunisian context, and to assess the clinical and imaging features, treatment, and outcomes. We retrospectively retrieved the medical records of patients with CI among 220 BS patients admitted to the hospital internal medicine department between February 2006 and April 2019, who fulfilled the International Study Group diagnostic criteria for BS. Ten patients (8 men, 2 women) were eligible for the study. Mean age was 37.3 years. Three patients had 2 isolated episodes of cardiac BS. The different types of CI were coronary artery disease (5/10), intracardiac thrombus (4/10), pericarditis (1/10), myocarditis (1/10), and myocardial fibrosis (1/10). Five patients had associated vascular involvement (50%). Medical treatment was based on corticosteroids and colchicine in all patients (100%), anticoagulants in 8 (80%), and cyclophosphamide followed by azathioprine in 9 (90%). The clinical course was favorable in 9 patients; 1 patient died. CI remains an important feature of BS because of its association with increased risk of mortality and morbidity. Therefore, early screening and detection with imaging methods are paramount. Also, better cooperation between rheumatologists and cardiologists could improve outcomes.
Guarda su PubMed
