91 results on '"Konstantinos Savvatis"'
Search Results
2. Ring-like LGE in Advanced Friedreich's Ataxia Cardiomyopathy
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Giulia Montrasio, MD, Marina Zaromytidou, MD, PhD, MSc, Paula Velazquez, MD, Joana Silva Ferreira, MD, Paola Giunti, and Konstantinos Savvatis, MD, PhD
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2024
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3. Pathogenic Truncating Filamin C Mutations Presenting as Acute Myocarditis
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Apostolos Vrettos, Polyvios Demetriades, Martín Ortiz, Pablo García-Pavía, MD, PhD, Fernando Domínguez, Maria Paz Suárez-Mier, Thomas Gossios, and Konstantinos Savvatis
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2024
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4. Updated knowledge and practical implementations of stress echocardiography in ischemic and non-ischemic cardiac diseases: An expert consensus of the Working Group of Echocardiography of the Hellenic Society of Cardiology
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Nikolaos P.E. Kadoglou, Constantinos H. Papadopoulos, Konstantinos G. Papadopoulos, Stefanos Karagiannis, Ilias Karabinos, Savvas Loizos, Anastasios Theodosis-Georgilas, Konstantina Aggeli, Kalliopi Keramida, Dimitrios Klettas, Stavros Kounas, George Makavos, Ilias Ninios, Ioannis Ntalas, Ignatios Ikonomidis, Vasilios Sahpekidis, Alexandros Stefanidis, Theodora Zaglavara, George Athanasopoulos, George Karatasakis, Stamatios Kyrzopoulos, Nikos Kouris, Alexandros Patrianakos, Ioannis Paraskevaidis, Loukianos Rallidis, Konstantinos Savvatis, Dimitrios Tsiapras, and Petros Nihoyannopoulos
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Stress echocardiography ,Coronary artery disease ,Nonischemic disease ,Cardiac valves ,Cardiomyopathy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Stress echocardiography (SE) is a well established and valid technique, widely used for the diagnostic evaluation of patients with ischemic and nonischemic cardiac diseases. This statement of the Echocardiography Working Group of the Hellenic Society of Cardiology summarizes the consensus of the writing group regarding the applications of SE, based on the expertise of their members and on a critical review of present medical literature. The main objectives of the consensus document include a comprehensive review of SE methodology and training—which focus on the preparation, the protocols used, the analysis of the SE images, and updated, evidence-based knowledge about SE applications on ischemic and nonischemic heart diseases, such as in cardiomyopathies, heart failure, and valvular heart disease.
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- 2022
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5. Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations
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Ros Quinlivan, Michela Guglieri, Ashish Chikermane, Adrian Morley-Davies, Konstantinos Savvatis, Zaheer Yousef, John Bourke, William Bradlow, Matthew Fenton, Caroline Coats, Maria Ilina, Marianela Schiava, Cathy Turner, Alexandra Johnson, Stam Kapetanakis, and Lisa Kuhwald
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Objective We provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in the DMD-gene.Methods Initiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD.Results The resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivan et al and are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society.Conclusion These guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.
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- 2022
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6. Is This the Prime Time for Transradial Access Left Ventricular Endomyocardial Biopsy?
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Zaccharie Tyler, Oliver P Guttmann, Konstantinos Savvatis, Daniel Jones, and Constantinos O’Mahony
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Surgery ,RD1-811 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Left ventricular endomyocardial biopsy (EMB) is an essential tool in the management of myocarditis and is conventionally performed via transfemoral access (TFA). Transradial access EMB (TRA-EMB) is a novel alternative and the authors sought to determine its safety and feasibility by conducting a systematic review of the literature. Medline was searched in 2020, and cohort demographics, procedural details and complications were extracted from selected studies. Four observational studies with a combined total of 496 procedures were included. TRA-EMB was most frequently performed with a sheathless MP1 guide catheter via the right radial artery. The most common complication was pericardial effusion (up to 11% in one study), but pericardial drainage for tamponade was rare (one reported case). Death and mitral valve damage have not been reported. TRA-EMB was successful in obtaining samples in 99% of reported procedures. The authors concluded that TRA-EMB is a safe and feasible alternative to TFA-EMB and the most common complication is uncomplicated pericardial effusion.
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- 2021
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7. Diagnostic Impact of Repeated Expert Review & Long‐Term Follow‐Up in Determining Etiology of Idiopathic Cardiac Arrest
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Ahmed Merghani, Christopher Monkhouse, Claire Kirkby, Konstantinos Savvatis, Saidi A. Mohiddin, Perry Elliott, Constantinos O’Mahony, Martin D. Lowe, Richard J. Schilling, and Pier D. Lambiase
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cardiomyopathy ,channelopathy ,defibrillators ,idiopathic ventricular fibrillation ,ischemic heart disease ,sudden cardiac death ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Recognizing the etiology of sudden cardiac arrest (SCA) has an enormous impact on the management of victims and their immediate families. A significant proportion of SCA survivors with a structurally normal heart are not offered a diagnosis and there is no clear consensus on the type and duration of follow‐up. We aimed to assess the utility of a multidisciplinary approach in optimizing diagnosis of cardiac arrest etiology during follow‐up. Methods and Results We retrospectively assessed 327 consecutive SCA survivors (mean age 61.9±16.2 years, 80% men) who underwent secondary prevention implantable cardioverter defibrillators between May 2015 and November 2018. The initial diagnosis was recorded at the time of admission and follow‐up diagnosis was deduced from subsequent clinic records, investigations, and outcomes of multidisciplinary team meetings. Structural heart disease accounted for 282 (86%) of SCAs. Forty‐five (14%) patients had a structurally normal heart and underwent comprehensive testing and follow‐up (mean duration 93±52 weeks). On initial evaluation, 14/45 (31%) of these received a diagnosis, rising to 29/45 (64%) with serial reviews during follow‐up. Discussion in multidisciplinary team meetings and imaging reassessment accounted for 47% of new diagnoses. No additional diagnoses were made beyond 96 weeks. Nineteen (5.8%) fatalities occurred in the entire cohort, exclusively in patients with structural heart disease. Conclusions Systematic comprehensive testing combined with multidisciplinary expert team review of SCA survivors without structural heart disease improves the yield and time to diagnosis compared with previously published studies. This approach has positive implications in the management of SCA survivors and their families.
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- 2021
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8. Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy
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Kapka Miteva, Kathleen Pappritz, Marzena Sosnowski, Muhammad El-Shafeey, Irene Müller, Fengquan Dong, Konstantinos Savvatis, Jochen Ringe, Carsten Tschöpe, and Sophie Van Linthout
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Medicine ,Science - Abstract
Abstract Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.
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- 2018
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9. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
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Jin Yang, Konstantinos Savvatis, Jong Seok Kang, Peidong Fan, Hongyan Zhong, Karen Schwartz, Vivian Barry, Amanda Mikels-Vigdal, Serge Karpinski, Dmytro Kornyeyev, Joanne Adamkewicz, Xuhui Feng, Qiong Zhou, Ching Shang, Praveen Kumar, Dillon Phan, Mario Kasner, Begoña López, Javier Diez, Keith C. Wright, Roxanne L. Kovacs, Peng-Sheng Chen, Thomas Quertermous, Victoria Smith, Lina Yao, Carsten Tschöpe, and Ching-Pin Chang
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Science - Abstract
Lysyl oxidase-like 2 (LOXL2) is an enzyme that promotes scaffolding of extracellular matrix proteins. Here the authors show that LOXL2 is crucial for pressure-overload induced cardiac fibrosis, and that antibody-mediated inhibition or genetic disruption ofLoxl2in mice shows therapeutic potential for treatment of cardiac fibrosis.
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- 2016
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10. CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis.
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Irene Müller, Kathleen Pappritz, Konstantinos Savvatis, Kerstin Puhl, Fengquan Dong, Muhammad El-Shafeey, Nazha Hamdani, Isabell Hamann, Michel Noutsias, Carmen Infante-Duarte, Wolfgang A Linke, Sophie Van Linthout, and Carsten Tschöpe
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Medicine ,Science - Abstract
Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced myocarditis.
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- 2017
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11. Cardiac Fibroblasts Aggravate Viral Myocarditis: Cell Specific Coxsackievirus B3 Replication
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Diana Lindner, Jia Li, Konstantinos Savvatis, Karin Klingel, Stefan Blankenberg, Carsten Tschöpe, and Dirk Westermann
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Pathology ,RB1-214 - Abstract
Myocarditis is an inflammatory disease caused by viral infection. Different subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inflammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: fibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3) and detected increased gene expression of anti-inflammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac fibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-α, IL-6, MCP-1, and IFN-β was significantly increased in cardiac fibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac fibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase) compared to cardiomyocytes (14-fold increase) between 6 and 24 hours after infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. Therefore, we suggest that cardiac fibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis.
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- 2014
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12. Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis.
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Konstantinos Savvatis, Sophie van Linthout, Kapka Miteva, Kathleen Pappritz, Dirk Westermann, Joerg C Schefold, Gerhard Fusch, Alice Weithäuser, Ursula Rauch, Peter-Moritz Becher, Karin Klingel, Jochen Ringe, Andreas Kurtz, Heinz-Peter Schultheiss, and Carsten Tschöpe
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Medicine ,Science - Abstract
Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFα, IL1β and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNγ in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs.
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- 2012
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13. High-Mobility Group Box-1 Protein Serum Levels Do Not Reflect Monocytic Function in Patients with Sepsis-Induced Immunosuppression
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Nadine Unterwalder, Christian Meisel, Konstantinos Savvatis, Ben Hammoud, Christina Fotopoulou, Hans-Dieter Volk, Petra Reinke, and Joerg C. Schefold
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Pathology ,RB1-214 - Abstract
Background. High-mobility group box-1 (HMGB-1) protein is released during “late sepsis” by activated monocytes. We investigated whether systemic HMGB-1 levels are associated with indices of monocytic activation/function in patients with sepsis-induced immunosuppression. Methodology. 36 patients (31 male, 64±14 years) with severe sepsis/septic shock and monocytic deactivation (reduced mHLA-DR expression and TNF-α release) were assessed in a subanalysis of a placebo-controlled immunostimulatory trial using GM-CSF. HMGB-1 levels were assessed over a 9-day treatment interval. Data were compared to standardized biomarkers of monocytic immunity (mHLA-DR expression, TNF-α release). Principle findings. HMGB-1 levels were enhanced in sepsis but did not differ between treatment and placebo groups at baseline (14.6 ± 13.5 versus 12.5 ± 11.5 ng/ml, P=.62). When compared to controls, HMGB-1 level increased transiently in treated patients at day 5 (27.8±21.7 versus 11.0±14.9, P=.01). Between group differences were not noted at any other point of assessment. HMGB-1 levels were not associated with markers of monocytic function or clinical disease severity. Conclusions. GM-CSF treatment for sepsis-induced immunosuppression induces a moderate but only transient increase in systemic HMGB-1 levels. HMGB-1 levels should not be used for monitoring of monocytic function in immunostimulatory trials as they do not adequately portray contemporary changes in monocytic immunity.
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- 2010
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14. 16 Impaired strain precedes fibrosis in lamin heart disease
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Constantin-Cristian Topriceanu, Mashael Al-Farih, Denis C Ilie-Ablachim, Matt Webber, George Joy, Stephen Pettit, Ben O’Brien, Alun D Hughes, Konstantinos Savvatis, Saidi Mohiddin, William Moody, Rick Steeds, Paolo E Puddu, Paolo Piras, James C Moon, Andrea Barison, and Gabriella Captur
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- 2023
15. An overview of heart rhythm disorders and management in myotonic dystrophy type 1
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Chris Turner, Rui Providência, Thomas D. Gossios, Konstantinos Savvatis, Antonio Creta, Karim Wahbi, Oliver R. Segal, Luis R. Lopes, and Nikoletta Nikolenko
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Adult ,medicine.medical_specialty ,Heart rhythm disorders ,medicine.medical_treatment ,Population ,Myotonic dystrophy ,Sudden cardiac death ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Myotonic Dystrophy ,Muscular dystrophy ,education ,Conduction disease ,education.field_of_study ,Supraventricular arrhythmia ,business.industry ,Arrhythmias, Cardiac ,Implantable cardioverter-defibrillator ,medicine.disease ,Death, Sudden, Cardiac ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet expansion of the noncoding region of the DMPK gene. Cardiac involvement is frequent, with conduction disease and supraventricular and ventricular arrhythmias being the most prevalent cardiac manifestations, often developing from a young age. The development of cardiac arrhythmias has been linked to increased morbidity and mortality, with sudden cardiac death well described. Strategies to mitigate risk of arrhythmic death have been developed. In this review, we outline the current knowledge on the pathophysiology of rhythm abnormalities in patients with myotonic dystrophy and summarize available knowledge on arrhythmic risk stratification. We also review management strategies from an electrophysiological perspective, attempting to underline the substantial unmet need to address residual arrhythmic risks for this population.
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- 2022
16. Andersen–Tawil syndrome: deep phenotyping reveals significant cardiac and neuromuscular morbidity
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Vinojini Vivekanandam, Roope Männikkö, Iwona Skorupinska, Louise Germain, Belinda Gray, Sarah Wedderburn, Damian Kozyra, Richa Sud, Natalie James, Sarah Holmes, Konstantinos Savvatis, Doreen Fialho, Ashirwad Merve, Jatin Pattni, Maria Farrugia, Elijah R Behr, Chiara Marini-Bettolo, Michael G Hanna, and Emma Matthews
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Andersen Syndrome ,Electrocardiography ,Phenotype ,Mutation ,Humans ,Genetic Testing ,Neurology (clinical) ,Morbidity - Abstract
Andersen–Tawil syndrome is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterized by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multisystem phenotype is not well described. In-depth, multisystem phenotyping is required to inform diagnosis and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognized, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fat accumulation on MRI and tubular aggregates on muscle biopsy, emphasizing the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing was not reliable in predicting neuromuscular symptoms. A normal long exercise test was seen in five patients, of whom four had episodic weakness. Sixty-seven per cent of patients treated with acetazolamide reported a good neuromuscular response. Thirteen per cent of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but Holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal Holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature; however, 8% of patients did not have dysmorphic features and one-third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that Andersen–Tawil syndrome is not benign. We report marked neuromuscular morbidity and cardiac risk with multisystem involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of Andersen–Tawil syndrome patients have no (or few) dysmorphic features or negative long exercise test. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.
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- 2021
17. Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity
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Silvia Fanti, Edward Stephenson, Etel Rocha-Vieira, Alexandros Protonotarios, Stavroula Kanoni, Eriomina Shahaj, M. Paula Longhi, Vishal S. Vyas, Carlene Dyer, Elena Pontarini, Angeliki Asimaki, Carlos Bueno-Beti, Monica De Gaspari, Stefania Rizzo, Cristina Basso, Michele Bombardieri, David Coe, Guosu Wang, Daniel Harding, Iain Gallagher, Egle Solito, Perry Elliott, Stephane Heymans, Maurits Sikking, Konstantinos Savvatis, Saidi A. Mohiddin, Federica M. Marelli-Berg, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Fanti, Silvia, Stephenson, Edward, Rocha-Vieira, Etel, Protonotarios, Alexandro, Kanoni, Stavroula, Shahaj, Eriomina, Longhi, M Paula, Vyas, Vishal S, Dyer, Carlene, Pontarini, Elena, Asimaki, Angeliki, Bueno-Beti, Carlo, De Gaspari, Monica, Rizzo, Stefania, Basso, Cristina, Bombardieri, Michele, Coe, David, Wang, Guosu, Harding, Daniel, Gallagher, Iain, Solito, Egle, Elliott, Perry, Heymans, Stephane, Sikking, Maurit, Savvatis, Konstantino, Mohiddin, Saidi A, and Marelli-Berg, Federica M
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cardiomyopathies ,T-lymphocyte ,mice ,Autoimmunity ,heart ,Autoimmune Diseases ,Memory T Cells ,T-lymphocytes ,cardiac myosins ,hepatocyte growth factor ,humans ,inflammation ,myocarditis ,therapeutics ,Physiology (medical) ,Humans ,Animals ,human ,Inflammation ,cardiomyopathie ,Myocardium ,Myocarditis ,myocarditi ,cardiac myosin ,Cardiology and Cardiovascular Medicine - Abstract
Background: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)–expressing (c-Met + ) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. Methods: In-depth phenotyping of peripheral blood T cells, including c-Met + T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. Results: We show that c-Met + T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met + T cells are distinct from those of c-Met–negative (c-Met − ) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met + T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met + T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met + T cells. Conclusions: Our study demonstrates that the detection of circulating c-Met + T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.
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- 2022
18. A Normal Electrocardiogram Does Not Exclude Infra-Hisian Conduction Disease in Patients With Myotonic Dystrophy Type 1
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Antonio Creta, Konstantinos Savvatis, Chris Turner, Rui Providência, Thomas D. Gossios, Perry M. Elliott, and Oliver R. Segal
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Adult ,Male ,Pacemaker, Artificial ,medicine.medical_specialty ,Disease ,030204 cardiovascular system & hematology ,Myotonic dystrophy ,Sudden death ,Sudden cardiac death ,Electrocardiography ,03 medical and health sciences ,Electrophysiology study ,QRS complex ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Myotonic Dystrophy ,In patient ,030212 general & internal medicine ,PR interval ,medicine.diagnostic_test ,business.industry ,Arrhythmias, Cardiac ,Middle Aged ,medicine.disease ,Death, Sudden, Cardiac ,Cardiology ,Female ,business - Abstract
This study aimed to identify electrocardiographic (ECG) predictors of a prolonged His-ventricular (HV) interval in patients with type 1 myotonic dystrophy (DM1).Patients with DM1 have an increased risk of sudden cardiac death. The presence of His-Purkinje system disease/prolonged HV interval (≥70 ms) is associated with a higher risk of potentially life-threatening bradyarrhythmic events.Electrophysiology studies (EPSs) were performed in all DM1 patients referred to 2 tertiary centers for routine cardiac assessment. In a subgroup of patients, the EPS was repeated at varying intervals.A total of 154 patients (mean age: 43.7 ± 13.3; 58.1% male) underwent 202 diagnostic EPSs. HV ≥70 ms was found on 58 EPSs (28.7%); 9 of 59 patients (15.2%) with PR 200 ms and QRS interval 110 ms on baseline ECG had an HV ≥70 ms on EPS. Among those with PR ≥200 ms and/or QRS interval ≥100 ms, only 33.9% had an HV ≥70 ms on EPS. There were 38 patients who underwent repeated EPS, in which 28.8% demonstrated a prolongation of the HV interval overall compared with baseline. QRS duration demonstrated the most powerful discriminative capacity for HV ≥70 ms (area under the receiver operating characteristic curve: 0.76; 95% confidence interval [CI]: 0.68 to 0.84; p 0.001). On multivariate analysis, QRS interval ≥112 ms had the highest predictive value for HV ≥70 ms (odds ratio: 7.94; 95% CI: 3.85 to 16.37.ECG parameters have a poor predictive value for infra-Hisian conduction block in DM1 patients. QRS and PR intervals are normal in up to 15.2% of DM1 patients with prolonged HV, and 66.1% of those with PR ≥200 ms and/or QRS ≥100 ms do not have advanced His-Purkinje conduction system disease on EPS. Electrophysiology testing should be a mandatory part of screening for all patients to guide prophylactic pacemaker implantation.
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- 2021
19. Deciphering hypertrophic cardiomyopathy with electrocardiography
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Thomas D. Gossios, Pavlos Rouskas, Thomas Zegkos, Despoina Parcharidou, Konstantinos Savvatis, Dimitrios Ntelios, Georgios K. Efthimiadis, and Haralambos Karvounis
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Phenocopy ,medicine.medical_specialty ,education.field_of_study ,Modalities ,medicine.diagnostic_test ,business.industry ,Population ,Hypertrophic cardiomyopathy ,Disease ,medicine.disease ,medicine ,Differential diagnosis ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business ,education ,Electrocardiography ,Genetic testing - Abstract
The comprehensive assessment of patients with hypertrophic cardiomyopathy is a complex process, with each step concurrently focusing on confirmation of the diagnosis, differentiation between sarcomeric and non-sarcomeric disease (phenocopy), and prognostication. Novel modalities such as genetic testing and advanced imaging have allowed for substantial advancements in the understanding of this condition and facilitate patient management. However, their availability is at present not universal, and interpretation requires a high level of expertise. In this setting, electrocardiography, a fast and widely available method, still retains a significant role in everyday clinical assessment of this population. In our review, we follow a stepwise approach for the interpretation of each electrocardiographic segment, discussing clinical implications of electrocardiographic patterns in sarcomeric disease, their value in the differential diagnosis from phenocopies, and impact on patient management. Outlining the substantial amount of information to be obtained from a simple tracing, we exhibit how electrocardiography is likely to remain an integral diagnostic tool in the future as well.
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- 2021
20. Long-term Safety and Efficacy of Mexiletine in Myotonic Dystrophy Types 1 and 2
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A.S. Carr, Susan MacDonald, Chris Turner, Christina Mousele, Emma Matthews, Michael G. Hanna, Robert D S Pitceathly, and Konstantinos Savvatis
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medicine.medical_specialty ,business.industry ,Research ,medicine.disease ,Myotonia ,Myotonic dystrophy ,Safety profile ,Internal medicine ,Mexiletine ,Medicine ,Effective treatment ,Neurology (clinical) ,Long term safety ,business ,Adverse effect ,medicine.drug - Abstract
Background and ObjectiveMyotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended antimyotonic agent in the nondystrophic myotonias, but its use in myotonic dystrophy is limited because of lack of data regarding its long-term efficacy and safety profile.MethodsTo address this issue, this study retrospectively evaluated patients with myotonic dystrophy receiving mexiletine over a mean time period of 32.9 months (range 0.1–216 months).ResultsThis study demonstrated that 96% of patients reported some improvement in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac adverse events were associated with the long-term use of mexiletine.ConclusionsThese findings support that mexiletine is both safe and effective when used long-term in myotonic dystrophy.Classification of EvidenceThis study provides Class IV evidence that mexiletine is a well-tolerated and effective treatment for myotonic dystrophy types 1 and 2.
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- 2021
21. The Myocardium in Aortic Stenosis Revisited
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Rocío Eiros, Patrizia Camelliti, Konstantinos Savvatis, Arantxa González, George Thornton, Thomas A. Treibel, Janos Kriston-Vizi, M Ashworth, James C. Moon, and Begoña López
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Noninvasive imaging ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Cardiomyopathy ,Magnetic resonance imaging ,030204 cardiovascular system & hematology ,equipment and supplies ,medicine.disease ,Myocardial function ,3. Good health ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Stenosis ,0302 clinical medicine ,Diffuse fibrosis ,Internal medicine ,cardiovascular system ,Cardiology ,medicine ,Myocyte ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,business - Abstract
Noninvasive imaging of myocardial function has limitations as a readout of myocardial biology and therefore as the basis for cardiomyopathy treatments. Measuring scar by using cardiovascular magnetic resonance (CMR) adds value but does not inform about non-scarred myocardium, the key therapeutic
- Published
- 2020
22. Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator
- Author
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Alexandros Protonotarios, Riccardo Bariani, Chiara Cappelletto, Menelaos Pavlou, Alba García-García, Alberto Cipriani, Ioannis Protonotarios, Adrian Rivas, Regitze Wittenberg, Maddalena Graziosi, Zafeirenia Xylouri, José M Larrañaga-Moreira, Antonio de Luca, Rudy Celeghin, Kalliopi Pilichou, Athanasios Bakalakos, Luis Rocha Lopes, Konstantinos Savvatis, Davide Stolfo, Matteo Dal Ferro, Marco Merlo, Cristina Basso, Javier Limeres Freire, Jose F Rodriguez-Palomares, Toru Kubo, Tomas Ripoll-Vera, Roberto Barriales-Villa, Loizos Antoniades, Jens Mogensen, Pablo Garcia-Pavia, Karim Wahbi, Elena Biagini, Aris Anastasakis, Adalena Tsatsopoulou, Esther Zorio, Juan R Gimeno, Jose Manuel Garcia-Pinilla, Petros Syrris, Gianfranco Sinagra, Barbara Bauce, Perry M Elliott, Protonotarios, Alexandro, Bariani, Riccardo, Cappelletto, Chiara, Pavlou, Menelao, García-García, Alba, Cipriani, Alberto, Protonotarios, Ioanni, Rivas, Adrian, Wittenberg, Regitze, Graziosi, Maddalena, Xylouri, Zafeirenia, Larrañaga-Moreira, José M, de Luca, Antonio, Celeghin, Rudy, Pilichou, Kalliopi, Bakalakos, Athanasio, Lopes, Luis Rocha, Savvatis, Konstantino, Stolfo, Davide, Dal Ferro, Matteo, Merlo, Marco, Basso, Cristina, Freire, Javier Limere, Rodriguez-Palomares, Jose F, Kubo, Toru, Ripoll-Vera, Toma, Barriales-Villa, Roberto, Antoniades, Loizo, Mogensen, Jen, Garcia-Pavia, Pablo, Wahbi, Karim, Biagini, Elena, Anastasakis, Ari, Tsatsopoulou, Adalena, Zorio, Esther, Gimeno, Juan R, Garcia-Pinilla, Jose Manuel, Syrris, Petro, Sinagra, Gianfranco, Bauce, Barbara, and Elliott, Perry M
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Arrhythmogenic Right Ventricular Dysplasia/genetics ,Arrhythmogenic right ventricular cardiomyopathy ,Genotype ,Risk stratification ,Sudden cardiac death ,Ventricular arrhythmia ,Arrhythmias, Cardiac ,Risk Assessment ,Death, Sudden, Cardiac ,Risk Factors ,Humans ,Cardiology and Cardiovascular Medicine ,Death, Sudden, Cardiac/epidemiology ,Arrhythmogenic Right Ventricular Dysplasia - Abstract
Aims To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9–3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.
- Published
- 2022
23. Cardiac Outcomes in Adults With Mitochondrial Diseases
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Konstantinos Savvatis, Christoffer Rasmus Vissing, Lori Klouvi, Anca Florian, Mehjabin Rahman, Anthony Béhin, Abdallah Fayssoil, Marion Masingue, Tanya Stojkovic, Henri Marc Bécane, Nawal Berber, Fanny Mochel, Denis Duboc, Bertrand Fontaine, Bjørg Krett, Caroline Stalens, Julie Lejeune, Robert D.S. Pitceathly, Luis Lopes, Malika Saadi, Thomas Gossios, Vincent Procaccio, Marco Spinazzi, Céline Tard, Pascal De Groote, Claire-Marie Dhaenens, Claire Douillard, Andoni Echaniz-Laguna, Ros Quinlivan, Michael G. Hanna, Ali Yilmaz, John Vissing, Pascal Laforêt, Perry Elliott, Karim Wahbi, Queen Mary University of London (QMUL), IT University of Copenhagen (ITU), Association française contre les myopathies (AFM-Téléthon), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University College of London [London] (UCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris Cité (UPCité), Sorbonne Université (SU), Hôpital Cochin [AP-HP], Aristotle University of Thessaloniki, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Claude Huriez [Lille], CHU Lille, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), MR/S005021/1, Association Française contre les Myopathies, AFM, Medical Research Council, MRC: MR/S002065/1, Department of Health and Social Care, DH, University College London Hospitals NHS Foundation Trust, UCLH, NIHR Cambridge Biomedical Research Centre, This study was funded by grants from the Association Française contre les Myopathies (French Alliance against Myopathies), which was not involved in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review or approval of the manuscript, and nor in the decision to submit the manuscript for publication. Dr Pitceathly is supported by a Medical Research Council (United Kingdom) Clinician Scientist Fellowship (MR/S002065/1). Drs Pitceathly and Hanna receive funding from a Medical Research Council (United Kingdom) strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1). Dr Lopes is supported by a Medical Research Council (United Kingdom) clinical academic partnership (CARP) award. Dr Quinlivan was funded by National Institute for Health and Care Research Biomedical Research Centre, University College Hospitals Foundation Trust. The University College London Hospitals/University College London Queen Square Institute of Neurology sequencing facility receives a proportion of funding from the Department of Health's National Institute for Health and Care Research Biomedical Research Centre’s funding scheme. The clinical and diagnostic 'Rare Mitochondrial Disorders' Service in London is funded by the U.K. NHS Highly Specialised Commissioners. Dr Elliott has received consultancy fees from Pfizer, Sanofi, Sarepta, DinaQor, Freeline, Novo Nordisk, and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Adult ,conduction disease ,mitochondrial diseases ,[SDV]Life Sciences [q-bio] ,heart failure ,sudden death ,Heart ,Stroke Volume ,Prognosis ,DNA, Mitochondrial ,Ventricular Function, Left ,single large-scale deletions ,Risk Factors ,Humans ,Hypertrophy, Left Ventricular ,Cardiology and Cardiovascular Medicine ,G%22">m3243A>G - Abstract
International audience; Background: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases. Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction
- Published
- 2022
24. Is This the Prime Time for Transradial Access Left Ventricular Endomyocardial Biopsy?
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Konstantinos Savvatis, Zaccharie Tyler, Oliver P Guttmann, Constantinos O'Mahony, and Daniel A. Jones
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medicine.medical_specialty ,Myocarditis ,RD1-811 ,medicine.diagnostic_test ,business.industry ,Transradial approach ,medicine.disease ,Pericardial effusion ,Endomyocardial biopsy ,Surgery ,medicine.anatomical_structure ,Structural ,RC666-701 ,Mitral valve ,Biopsy ,Cohort ,medicine ,Diseases of the circulatory (Cardiovascular) system ,biopsy ,Tamponade ,myocarditis ,Cardiology and Cardiovascular Medicine ,business ,Complication - Abstract
Left ventricular endomyocardial biopsy (EMB) is an essential tool in the management of myocarditis and is conventionally performed via transfemoral access (TFA). Transradial access EMB (TRA-EMB) is a novel alternative and the authors sought to determine its safety and feasibility by conducting a systematic review of the literature. Medline was searched in 2020, and cohort demographics, procedural details and complications were extracted from selected studies. Four observational studies with a combined total of 496 procedures were included. TRA-EMB was most frequently performed with a sheathless MP1 guide catheter via the right radial artery. The most common complication was pericardial effusion (up to 11% in one study), but pericardial drainage for tamponade was rare (one reported case). Death and mitral valve damage have not been reported. TRA-EMB was successful in obtaining samples in 99% of reported procedures. The authors concluded that TRA-EMB is a safe and feasible alternative to TFA-EMB and the most common complication is uncomplicated pericardial effusion.
- Published
- 2021
25. Reply: Myotonic Dystrophy and Conduction Disease
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Antonio, Creta, Rui, Providência, Thomas, Gossios, Perry, Elliott, Chris, Turner, Konstantinos, Savvatis, and Oliver R, Segal
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Cardiac Conduction System Disease ,Humans ,Myotonic Dystrophy - Published
- 2021
26. Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations
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John Bourke, Cathy Turner, William Bradlow, Ashish Chikermane, Caroline Coats, Matthew Fenton, Maria Ilina, Alexandra Johnson, Stam Kapetanakis, Lisa Kuhwald, Adrian Morley-Davies, Ros Quinlivan, Konstantinos Savvatis, Marianela Schiava, Zaheer Yousef, and Michela Guglieri
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Adult ,Muscular Dystrophy, Duchenne ,Heterozygote ,Mutation ,Humans ,Female ,Heart ,Cardiomyopathies ,Child ,Cardiology and Cardiovascular Medicine - Abstract
ObjectiveWe provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in theDMD-gene.MethodsInitiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD.ResultsThe resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivanet aland are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society.ConclusionThese guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.
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- 2022
27. Diagnostic Impact of Repeated Expert ReviewLong-Term Follow-Up in Determining Etiology of Idiopathic Cardiac Arrest
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Pier D. Lambiase, Ahmed Merghani, Constantinos O'Mahony, Claire Kirkby, Richard J. Schilling, Saidi A Mohiddin, Martin Lowe, Christopher Monkhouse, Konstantinos Savvatis, and Perry M. Elliott
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Male ,Time Factors ,Cardiomyopathy ,Diagnostic Techniques, Cardiovascular ,030204 cardiovascular system & hematology ,Arrhythmias ,Sudden cardiac death ,0302 clinical medicine ,Risk Factors ,defibrillators ,Secondary Prevention ,Idiopathic cardiac arrest ,Arrhythmia and Electrophysiology ,030212 general & internal medicine ,Registries ,Idiopathic ventricular fibrillation ,Original Research ,Middle Aged ,Prognosis ,Defibrillators, Implantable ,Ventricular Fibrillation ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Heart Diseases ,Long term follow up ,Electric Countershock ,sudden cardiac death ,03 medical and health sciences ,Young Adult ,channelopathy ,Channelopathy ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Patient Care Team ,business.industry ,Sudden cardiac arrest ,medicine.disease ,ischemic heart disease ,Death, Sudden, Cardiac ,Etiology ,business ,cardiomyopathy ,Catheter Ablation and Implantable Cardioverter-Defibrillator ,idiopathic ventricular fibrillation - Abstract
Background Recognizing the etiology of sudden cardiac arrest (SCA) has an enormous impact on the management of victims and their immediate families. A significant proportion of SCA survivors with a structurally normal heart are not offered a diagnosis and there is no clear consensus on the type and duration of follow‐up. We aimed to assess the utility of a multidisciplinary approach in optimizing diagnosis of cardiac arrest etiology during follow‐up. Methods and Results We retrospectively assessed 327 consecutive SCA survivors (mean age 61.9±16.2 years, 80% men) who underwent secondary prevention implantable cardioverter defibrillators between May 2015 and November 2018. The initial diagnosis was recorded at the time of admission and follow‐up diagnosis was deduced from subsequent clinic records, investigations, and outcomes of multidisciplinary team meetings. Structural heart disease accounted for 282 (86%) of SCAs. Forty‐five (14%) patients had a structurally normal heart and underwent comprehensive testing and follow‐up (mean duration 93±52 weeks). On initial evaluation, 14/45 (31%) of these received a diagnosis, rising to 29/45 (64%) with serial reviews during follow‐up. Discussion in multidisciplinary team meetings and imaging reassessment accounted for 47% of new diagnoses. No additional diagnoses were made beyond 96 weeks. Nineteen (5.8%) fatalities occurred in the entire cohort, exclusively in patients with structural heart disease. Conclusions Systematic comprehensive testing combined with multidisciplinary expert team review of SCA survivors without structural heart disease improves the yield and time to diagnosis compared with previously published studies. This approach has positive implications in the management of SCA survivors and their families.
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- 2021
28. Iterative Reanalysis of Hypertrophic Cardiomyopathy Exome Data Reveals Causative Pathogenic Mitochondrial DNA Variants
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Petros Syrris, Enrico Bugiardini, Cathy E. Woodward, Michael G. Hanna, Marta Futema, Joanna Jager, Robert D S Pitceathly, Alan Pittman, Perry M. Elliott, Reem Salem, David Murphy, Luis R. Lopes, Mohammed M Akhtar, and Konstantinos Savvatis
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Adult ,Male ,Genetics ,Mitochondrial DNA ,RNA, Transfer, Leu ,Mitochondrial disease ,Hypertrophic cardiomyopathy ,NADH Dehydrogenase ,General Medicine ,Cardiomyopathy, Hypertrophic ,Middle Aged ,Biology ,medicine.disease ,DNA, Mitochondrial ,Magnetic Resonance Imaging ,Electrocardiography ,Exome Sequencing ,medicine ,Humans ,Point Mutation ,Female ,Exome ,Aged - Published
- 2021
29. Updated knowledge and practical implementations of stress echocardiography in ischemic and non-ischemic cardiac diseases: An expert consensus of the Working Group of Echocardiography of the Hellenic Society of Cardiology
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Nikolaos P.E. Kadoglou, Constantinos H. Papadopoulos, Konstantinos G. Papadopoulos, Stefanos Karagiannis, Ilias Karabinos, Savvas Loizos, Anastasios Theodosis-Georgilas, Konstantina Aggeli, Kalliopi Keramida, Dimitrios Klettas, Stavros Kounas, George Makavos, Ilias Ninios, Ioannis Ntalas, Ignatios Ikonomidis, Vasilios Sahpekidis, Alexandros Stefanidis, Theodora Zaglavara, George Athanasopoulos, George Karatasakis, Stamatios Kyrzopoulos, Nikos Kouris, Alexandros Patrianakos, Ioannis Paraskevaidis, Loukianos Rallidis, Konstantinos Savvatis, Dimitrios Tsiapras, and Petros Nihoyannopoulos
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medicine.medical_specialty ,Consensus ,Heart Diseases ,business.industry ,valvular heart disease ,Cardiomyopathy ,Cardiology ,Expert consensus ,medicine.disease ,Coronary artery disease ,Echocardiography ,Heart failure ,Internal medicine ,Stress Echocardiography ,Medicine ,Humans ,Non ischemic ,Cardiology and Cardiovascular Medicine ,business ,Medical literature ,Echocardiography, Stress - Abstract
Stress echocardiography (SE) is a well-established and valid technique, widely-used for the diagnostic evaluation of patients with ischemic and non-ischemic cardiac diseases. This statement of the Echocardiography Working Group of the Hellenic Society of Cardiology summarizes the consensus of the writing group regarding the applications of SE, based on the expertise of their members and on a critical review of current medical literature. The main objectives of the consensus document include a comprehensive review of SE methodology and training, focusing on the preparation, the protocols used and the analysis of the SE images and an updated, evidence-based knowledge about SE applications on ischemic and non-ischemic heart diseases, such as in cardiomyopathies, heart failure and valvular heart disease.
- Published
- 2021
30. Clinical outcome of SARS-CoV-2 infection in 7 adults with Duchenne Muscular Dystrophy attending a specialist neuromuscular centre
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A. Pietrusz, Konstantinos Savvatis, Ros Quinlivan, Francis Cruces, and M. Desikan
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Duchenne muscular dystrophy ,SARS-Cov-2 ,Cardiomyopathy ,Anosmia ,Duchenne Muscular Dystrophy ,Asymptomatic ,Article ,03 medical and health sciences ,0302 clinical medicine ,DMD ,medicine ,Sore throat ,Genetics (clinical) ,Nose ,business.industry ,COVID-19 ,Cardiorespiratory fitness ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,medicine.symptom ,Complication ,business ,030217 neurology & neurosurgery - Abstract
Due to their frailty and cardiorespiratory compromise adults with DMD are considered extremely vulnerable and at high risk of severe infection should they contract COVID-19. We report 7 adults with DMD aged 17-26 years who tested positive on a nasopharyngeal PCR swab for SARS-CoV-2. Despite long term corticosteroid treatment, severe respiratory compromise requiring night-time ventilation and receiving treatment for moderate to severe cardiomyopathy, none of the patients developed moderate to severe symptoms; in fact two remained asymptomatic and two developed only anosmia and reduced sensation. The remaining three developed transient fever with or without sore throat, cough and runny nose. All recovered fully without complication and no patient required hospitalization.
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- 2021
31. Cardiac magnetic resonance assessment of progressive myo-pericarditis due to cobalt cardiotoxicity
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Mohammed Y Khanji, Charlotte Manisty, Luis R. Lopes, Massimiliano Lorenzini, and Konstantinos Savvatis
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Cardiotoxicity ,Magnetic Resonance Spectroscopy ,medicine.diagnostic_test ,business.industry ,chemistry.chemical_element ,Magnetic resonance imaging ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Cobalt ,medicine.disease ,Magnetic Resonance Imaging ,Pericarditis ,Myocarditis ,Nuclear magnetic resonance ,chemistry ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine ,Cardiac magnetic resonance ,business - Published
- 2020
32. The Safety and Feasibility of Transitioning From Transfemoral to Transradial Access Left Ventricular Endomyocardial Biopsy
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Zaccharie, Tyler, Oliver P, Guttmann, Mehul, Dhinoja, Rodnie, Oro, Konstantinos, Savvatis, Saidi, Mohiddin, Neha, Sekhri, Luis, Lopes, Vimal, Patel, Daniel A, Jones, Christos V, Bourantas, Anthony, Mathur, Perry M, Elliott, and Constantinos, O'Mahony
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Adult ,Femoral Artery ,Cardiac Catheterization ,Treatment Outcome ,Biopsy ,Radial Artery ,Feasibility Studies ,Humans ,Prospective Studies ,Middle Aged - Abstract
Left ventricular endomyocardial biopsy (LVEMB) is commonly performed via the transfemoral route. Radial access may help reduce vascular access complications, but there are few data on the safety and feasibility of transradial LVEMB.Describe the safety and feasibility of transitioning from transfemoral to transradial access LVEMB.This is a single-center, prospective, observational cohort study. Fifty procedures in 49 patients were included, 25 (50%) via the femoral route and 25 (50%) via the radial route.The cohort had a mean age of 47 ± 13 years and the most common indication for LVEMB was myocarditis. From June 2015 until September 2016, all procedures (n = 21) were performed via the femoral approach; thenceforth, there was a gradual transition to the radial approach. More tissue samples were obtained when the procedure was performed via the femoral approach (P.01). The minimum sampling target of 3 specimens was not met in 4 patients (16%) via the radial approach and in 1 patient (4%) via the femoral approach. Complications occurred in 3/25 transradial procedures (12%; 2 cardiac perforations and 1 forearm hematoma) and 3/25 transfemoral procedures (12%; 1 cardiac perforation, 1 femoral artery pseudoaneurysm, and 1 ventricular fibrillation). Cardiac perforations via the transradial approach occurred during the early transition period. There were no deaths.Transradial LVEMB is feasible, with a similar complication profile to femoral procedures, but associated with a smaller number of specimens. Transitioning from transfemoral to transradial procedures may initially be associated with a higher risk of complications and potentially a lower diagnostic yield.
- Published
- 2020
33. Saw-tooth cardiomyopathy: cardiomyopathies baring their teeth
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Konstantinos Savvatis, Alvaro Garcia-Ropero, and Dimitra Antonakaki
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medicine.medical_specialty ,business.industry ,Internal medicine ,Cardiology ,Cardiomyopathy ,Humans ,Medicine ,General Medicine ,Cardiomyopathy, Hypertrophic ,Cardiomyopathies ,business ,medicine.disease - Published
- 2022
34. The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy
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Mohammed M Akhtar, Hendrik Milting, Caroline Stanasiuk, Konstantinos Savvatis, Alexandros Protonotarios, Volker Walhorn, Marta Futema, Michael Ashworth, Dario Anselmetti, Petros Syrris, Sandra Ratnavadivel, Angeliki Asimaki, Andreas Brodehl, Joanna Jager, Perry M. Elliott, Thomas D. Gossios, Luis R. Lopes, and Ellie Quinn
- Subjects
Proband ,Male ,Pathology ,medicine.medical_specialty ,Ventricular Dysfunction, Right ,Cardiomyopathy ,Mutation, Missense ,030204 cardiovascular system & hematology ,Gene mutation ,Muscular Dystrophies ,Sudden cardiac death ,Desmin ,03 medical and health sciences ,Ventricular Dysfunction, Left ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,business.industry ,Genetic Carrier Screening ,Myocardium ,Myocardial Disorder ,Middle Aged ,medicine.disease ,Endomyocardial Fibrosis ,Phenotype ,United Kingdom ,Death, Sudden, Cardiac ,Functional Status ,Heart Function Tests ,Ventricular Fibrillation ,Myocardial fibrosis ,Female ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyopathies - Abstract
BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC, but with insufficient evidence to support their pathogenicity.; METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutation were prospectively screened by whole exome sequencing.; RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in three index patients (2%). We assessed the clinical phenotypes within their families and confirmed co-segregation. One carrier required heart transplantation, two died suddenly and one died of non-cardiac causes. All cases had right and left ventricular (LV) involvement. LV late gadolinium enhancement was present in all and circumferential sub-epicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short proto-filaments and small fibrous aggregates.; CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis. Copyright © 2020. Published by Elsevier Inc.
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- 2020
35. Risk Prediction Models and Scores in Hypertrophic Cardiomyopathy
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Thomas Zegkos, Thomas D. Gossios, Haralambos Karvounis, Despina G. Parcharidou, Konstantinos Savvatis, and Georgios Efthimiadis
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Pharmacology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Hypertrophic cardiomyopathy ,Cardiomyopathy, Hypertrophic ,Implantable cardioverter-defibrillator ,medicine.disease ,Risk prediction models ,Sudden death ,Risk Assessment ,Sudden cardiac death ,Defibrillators, Implantable ,Natural history ,Death, Sudden, Cardiac ,Risk Factors ,Drug Discovery ,Medicine ,Humans ,Personalized medicine ,business ,Intensive care medicine ,Genetic testing - Abstract
Hypertrophic cardiomyopathy (HCM) has historically been linked with sudden cardiac death (SCD). Currently, it is well established that only a subset of patients is at the highest risk stratum for such a catastrophic event. Detection of patients belonging to this high-risk category can allow for timely defibrillator implantation, changing the natural history of HCM. Inversely, device implantation in patients deemed at low risk leads to an unnecessary burden of device complications with no apparent protective benefit. Previous studies have identified a series of markers, now considered established risk factors, with genetic testing and newer imaging allowing for the detection of novel, highly promising indices of increased risk for SCD. Despite the identification of a number of risk factors, there is noticeable discrepancy in the utility of such factors for risk stratification between the current American and European guidelines. We sought to systematically review the data available on these two approaches, presenting their rationale and respective predictive capacity, also discussing the potential of novel markers to augment the precision of currently used risk stratification models for SCD in HCM.
- Published
- 2020
36. The Myocardium in Aortic Stenosis Revisited: More Complex Than Just Myocytes and Interstitial Diffuse Fibrosis
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Patrizia, Camelliti, Janos, Kriston-Vizi, Rocío, Eiros, George D, Thornton, Konstantinos, Savvatis, Michael A, Ashworth, Begoña, Lopez, Arantxa, González, James C, Moon, and Thomas A, Treibel
- Subjects
Muscle Cells ,Predictive Value of Tests ,Myocardium ,Humans ,Aortic Valve Stenosis ,Fibrosis - Published
- 2020
37. Early Treatment of Coxsackievirus B3-Infected Animals With Soluble Coxsackievirus-Adenovirus Receptor Inhibits Development of Chronic Coxsackievirus B3 Cardiomyopathy
- Author
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Karin Klingel, Carsten Tschöpe, Babette Dieringer, Jens Kurreck, Antje Beling, Robert Klopfleisch, Sandra Pinkert, Sophie Van Linthout, Konstantinos Savvatis, Henry Fechner, and Markian Pryshliak
- Subjects
Male ,Myocarditis ,Immunoconjugates ,Recombinant Fusion Proteins ,Cardiomyopathy ,Coxsackievirus Infections ,030204 cardiovascular system & hematology ,Coxsackievirus ,Antiviral Agents ,Ventricular Function, Left ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Receptor ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Myocardium ,Antiviral therapy ,Dilated cardiomyopathy ,Viral Load ,medicine.disease ,biology.organism_classification ,Virology ,Fibrosis ,Enterovirus B, Human ,Disease Models, Animal ,Acute myocarditis ,Coxsackievirus b3 ,Immunoglobulin G ,Chronic Disease ,Receptors, Virus ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyopathies - Abstract
Background: Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model. Methods: NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection. Results: Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P =0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P =0.02; dP/dt max , 7275.2±1674 versus 4432.6±1107 mm Hg/s, P =0.004; dP/dt min , −4046.9±776 versus −3146.3±642 mm Hg/s, P =0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury. Conclusions: Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.
- Published
- 2019
38. Reply
- Author
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Antonio Creta, Rui Providência, Thomas Gossios, Perry Elliott, Chris Turner, Konstantinos Savvatis, and Oliver R. Segal
- Published
- 2021
39. Myocardial strain analysis in family screening for genetic dilated cardiomyopathy: Testing the boundaries of normality?
- Author
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Konstantinos Savvatis and Alexandros Protonotarios
- Subjects
Cardiomyopathy, Dilated ,medicine.medical_specialty ,Genotype ,business.industry ,media_common.quotation_subject ,Cardiomyopathy ,Dilated cardiomyopathy ,medicine.disease ,Phenotype ,Internal medicine ,Myocardial strain ,Prevalence ,medicine ,Cardiology ,Humans ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,business ,Normality ,media_common - Published
- 2021
40. Complete regression of multiple biventricular thrombi in dilated cardiomyopathy: the role of cardiovascular magnetic resonance imaging for diagnosis and assessing treatment response
- Author
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Mohammed Y Khanji, Marta Fonseca, and Konstantinos Savvatis
- Subjects
Cardiomyopathy, Dilated ,Treatment response ,medicine.medical_specialty ,Images In… ,medicine.diagnostic_test ,business.industry ,Left bundle branch block ,Peripheral edema ,Thrombosis ,Magnetic resonance imaging ,Dilated cardiomyopathy ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Heart failure ,Internal medicine ,Complete regression ,Cardiology ,Humans ,Medicine ,Alcohol intake ,medicine.symptom ,business - Abstract
A 40-year-old man presented with a 7-day history of progressive breathlessness, orthopnoea and peripheral oedema. He had a history of excess alcohol intake, cannabis use and learning difficulties. The electrocardiogram revealed left bundle branch block ([figure 1A][1]). ![Figure 1][2] Figure
- Published
- 2021
41. Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: a comprehensive genotype-imaging phenotype study
- Author
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Konstantinos Savvatis, Alexandros Protonotarios, James C. Moon, Thomas D. Gossios, Mohammed M Akhtar, Thomas A. Treibel, Luis R. Lopes, Perry M. Elliott, Gabriella Captur, Petros Syrris, João B Augusto, Eleni Nakou, Rocío Eiros, Sara Moura-Ferreira, and Saidi A Mohiddin
- Subjects
Cardiomyopathy, Dilated ,medicine.medical_specialty ,Genotype ,Cardiomyopathy ,Contrast Media ,Gadolinium ,030204 cardiovascular system & hematology ,Ventricular tachycardia ,Ventricular Function, Left ,Sudden cardiac death ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,030212 general & internal medicine ,FLNC ,Ejection fraction ,biology ,medicine.diagnostic_test ,business.industry ,Desmoplakin ,Stroke Volume ,Dilated cardiomyopathy ,General Medicine ,medicine.disease ,Phenotype ,cardiovascular system ,Cardiology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Electrocardiography - Abstract
Aims Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC. Methods and results Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1.5 n = 2, and sarcomeric genes n = 7] were comprehensively phenotyped. Clustering analysis resulted in two groups: ‘DSP/FLNC genotypes’ and ‘non-DSP/FLNC’. There were no significant differences in age, sex, symptoms, baseline electrocardiography, arrhythmia burden, or ventricular volumes between the two groups. Subepicardial LV late gadolinium enhancement with ring-like pattern (at least three contiguous segments in the same short-axis slice) was observed in 78.1% of DSP/FLNC genotypes but was absent in the other DCM genotypes (P Conclusion DSP/FLNC genotypes cause more regionality in LV impairment. The most defining characteristic is a subepicardial ring-like scar pattern in DSP/FLNC, which should be considered in future diagnostic criteria for ALVC.
- Published
- 2019
42. 325Arrhythmogenic left ventricular cardiomyopathy and dilated cardiomyopathy: genotype-phenotype correlations
- Author
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T D Gossios, Konstantinos Savvatis, A Protonotarios, Perry M. Elliott, Rocío Eiros, James C. Moon, E Nakou, Petros Syrris, G Captur, Mohammed M Akhtar, J A Bicho Augusto, Sara Moura-Ferreira, Saidi A Mohiddin, Thomas A. Treibel, and Luis R. Lopes
- Subjects
medicine.medical_specialty ,business.industry ,Cardiomyopathy ,Dilated cardiomyopathy ,General Medicine ,medicine.disease ,Phenotype ,Ventricular cardiomyopathy ,Internal medicine ,Genotype ,medicine ,Cardiology ,Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine ,business ,Genotype-Phenotype Correlations - Published
- 2019
43. Maximal-effort cytoreductive surgery for ovarian cancer patients with a high tumor burden: variations in practice and impact on outcome
- Author
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Owen Owens, Paula Cunnea, Maria Kyrgiou, Ignacio Vazquez, Gordon J. S. Rustin, Marcia Hall, A Farthing, Neale Watson, Christina Fotopoulou, Richard Stümpfle, Hani Gabra, Jonathan Krell, Kuhan Hariharan, Jeremy Campbell, Malcolm Padwick, Katherine Nixon, and Konstantinos Savvatis
- Subjects
medicine.medical_specialty ,SOCIETY ,Carcinoma, Ovarian Epithelial ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,Internal medicine ,medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Survival rate ,Peritoneal Neoplasms ,Ovarian Neoplasms ,Science & Technology ,Performance status ,Proportional hazards model ,business.industry ,Hazard ratio ,WOMEN ,Retrospective cohort study ,Cytoreduction Surgical Procedures ,Gynecologic Oncology ,medicine.disease ,Confidence interval ,COMPLEX SURGERY ,Oncology ,030220 oncology & carcinogenesis ,SURVIVAL ,030211 gastroenterology & hepatology ,Female ,Surgery ,Ovarian cancer ,business ,Life Sciences & Biomedicine - Abstract
Background This study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC). Methods A retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied. Cox regression analysis identified the impact of treatment methods on survival. Results The study identified 249 patients (127 at center A and 122 in centre B) without significant differences in International Federation of Gynecology and Obstetrics (FIGO) stage (FIGO 4, 29.7% at centers A and B), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG
- Published
- 2019
44. Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress
- Author
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Dirk Westermann, Carsten Tschöpe, Ursula Rauch, Ulf Landmesser, Heinz-Peter Schultheiss, Andrea Dörner, Inga Klumpe, and Konstantinos Savvatis
- Subjects
Male ,0301 basic medicine ,Cell Survival ,Primary Cell Culture ,Myocardial Infarction ,Mitochondrion ,medicine.disease_cause ,Mitochondria, Heart ,Protein Carbonylation ,03 medical and health sciences ,0302 clinical medicine ,Adenine Nucleotide Translocator 1 ,Drug Discovery ,medicine ,Animals ,Myocytes, Cardiac ,Inner mitochondrial membrane ,Genetics (clinical) ,Membrane Potential, Mitochondrial ,Cardioprotection ,chemistry.chemical_classification ,Aldehydes ,Reactive oxygen species ,biology ,Caspase 3 ,Chemistry ,Cytochromes c ,Hydrogen Peroxide ,Catalase ,Survival Analysis ,Molecular biology ,Cell Hypoxia ,ANT ,Rats ,Oxidative Stress ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Rats, Transgenic ,Reactive Oxygen Species ,Oxidative stress ,Signal Transduction - Abstract
Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia.ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.
- Published
- 2016
45. Maximal effort cytoreductive surgery for disseminated ovarian cancer in a UK setting: challenges and possibilities
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Hani Gabra, Maria Kyrgiou, Benjamin P Jones, Long R. Jiao, Richard Stümpfle, A Farthing, Christina Fotopoulou, Marcia Hall, Rene Roux, Gordon J. S. Rustin, Konstantinos Savvatis, Jeremy Campbell, and Stephen J. Brett
- Subjects
Adult ,medicine.medical_specialty ,Pleural effusion ,medicine.medical_treatment ,Splenectomy ,Carcinoma, Ovarian Epithelial ,Anastomosis ,Multivisceral ,law.invention ,Cytoreduction ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Ovarian cancer ,law ,Cytoreduction Surgical Procedures ,1114 Paediatrics And Reproductive Medicine ,medicine ,Humans ,Neoplasms, Glandular and Epithelial ,Prospective Studies ,Oncology & Carcinogenesis ,030212 general & internal medicine ,Mortality ,Obstetrics & Reproductive Medicine ,Prospective cohort study ,Aged ,Aged, 80 and over ,Ovarian Neoplasms ,business.industry ,Albumin ,Obstetrics and Gynecology ,General Medicine ,Bowel resection ,Middle Aged ,medicine.disease ,Intensive care unit ,Surgery ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,Lymphadenectomy ,Morbidity ,business ,1112 Oncology And Carcinogenesis - Abstract
© 2016 Springer-Verlag Berlin HeidelbergObjective: To assess surgical morbidity and mortality of maximal effort cytoreductive surgery for disseminated epithelial ovarian cancer (EOC) in a UK tertiary center. Methods/materials: A monocentric prospective analysis of surgical morbidity and mortality was performed for all consecutive EOC patients who underwent extensive cytoreductive surgery between 01/2013 and 12/2014. Surgical complexity was assessed by the Mayo clinic surgical complexity score (SCS). Only patients with high SCS ≥5 were included in the analysis. Results: We evaluated 118 stage IIIC/IV patients, with a median age of 63 years (range 19–91); 47.5 % had ascites and 29 % a pleural effusion. Median duration of surgery was 247 min (range 100–540 min). Median surgical complexity score was 10 (range 5–15) consisting of bowel resection (71 %), stoma formation (13.6 %), diaphragmatic stripping/resection (67 %), liver/liver capsule resection (39 %), splenectomy (20 %), resection stomach/lesser sac (26.3 %), pleurectomy (17 %), coeliac trunk/subdiaphragmatic lymphadenectomy (8 %). Total macroscopic tumor clearance rate was 89 %. Major surgical complication rate was 18.6 % (n = 22), with a 28-day and 3-month mortality of 1.7 and 3.4 %, respectively. The anastomotic leak rate was 0.8 %; fistula/bowel perforation 3.4 %; thromboembolism 3.4 % and reoperation 4.2 %. Median intensive care unit and hospital stay were 1.7 (range 0–104) and 8 days (range 4–118), respectively. Four patients (3.3 %) failed to receive chemotherapy within the first 8 postoperative weeks. Conclusions: Maximal effort cytoreductive surgery for EOC is feasible within a UK setting with acceptable morbidity, low intestinal stoma rates and without clinically relevant delays to postoperative chemotherapy. Careful patient selection, and coordinated multidisciplinary effort appear to be the key for good outcome. Future evaluations should include quality of life analyses.
- Published
- 2016
46. Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction
- Author
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Bernhard H. Rauch, Konstantinos Savvatis, Peter Bobbert, Ursula Rauch, Verena Moos, Carsten Tschöpe, Michael Gotthardt, Dirk Lassner, Heinz-Peter Schutheiss, Marco Witkowski, Stephan B. Felix, Termeh Tabaraie, Andrea Dörner, Alice Weithauser, Michael H. Radke, Max Wegner, Ulf Landmesser, Julian Friebel, Mario Kasner, and Diana Bösel
- Subjects
Male ,medicine.medical_specialty ,Cardiac fibrosis ,Diastole ,Inflammation ,030204 cardiovascular system & hematology ,Endothelial activation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fibrosis ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Animals ,Humans ,Receptor, PAR-2 ,Protease-activated receptor 2 ,030304 developmental biology ,Aged ,Mice, Knockout ,0303 health sciences ,Heart Failure, Diastolic ,business.industry ,Myocardium ,Middle Aged ,medicine.disease ,Endocrinology ,Myocardial fibrosis ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Heart failure with preserved ejection fraction ,Cardiomyopathies - Abstract
Aims Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). Methods and results Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = −0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-β)-dependent signalling. This enhanced TGF-β/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). Conclusions Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF.
- Published
- 2018
47. P.123Frequency of coronary artery disease in people with McArdle disease
- Author
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Chiara Pizzamiglio, Richard Godfrey, T. Gkosios, S. Chatfield, Rosaline Quinlivan, M. Patasin, Renata S Scalco, J. Pattni, Konstantinos Savvatis, A. Pietrusz, and P. Elliott
- Subjects
Coronary artery disease ,medicine.medical_specialty ,MCARDLE DISEASE ,Neurology ,business.industry ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Cardiology ,Neurology (clinical) ,business ,medicine.disease ,Genetics (clinical) - Published
- 2019
48. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis
- Author
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Konstantinos Savvatis, Kathleen Pappritz, Javier Díez, Sophie Van Linthout, Christine Brandt, Petra Reinke, Begoña López, Henry Fechner, Arantxa González, Carsten Tschöpe, Fengquan Dong, Susana Ravassa, Hans-Dieter Volk, Karin Klingel, Irene Müller, Kapka Miteva, and Bahtiyar Kerim
- Subjects
0301 basic medicine ,Chemokine ,Regulatory T cell ,viruses ,Inflammation ,030204 cardiovascular system & hematology ,Coxsackievirus ,Biochemistry ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Medicine ,Molecular Biology ,biology ,business.industry ,Monocyte ,virus diseases ,biology.organism_classification ,030104 developmental biology ,medicine.anatomical_structure ,Monocyte differentiation ,Immunology ,cardiovascular system ,biology.protein ,Myelopoiesis ,medicine.symptom ,business ,Biotechnology - Abstract
Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Muller, I., Brandt, C., Lopez, B., Gonzalez, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschope, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.
- Published
- 2018
49. Dilated cardiomyopathy due to BLC2-associated athanogene 3 (BAG3) mutations
- Author
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Fernando Domínguez, Sofía Cuenca, Zofia Bilińska, Rocío Toro, Eric Villard, Roberto Barriales-Villa, Juan Pablo Ochoa, Folkert Asselbergs, Arjan Sammani, Maria Franaszczyk, Mohammed Akhtar, Maria José Coronado-Albi, Diego Rangel-Sousa, Jose F. Rodriguez-Palomares, Juan Jiménez-Jáimez, José Manuel Garcia-Pinilla, Tomás Ripoll-Vera, Maria Victoria Mogollón-Jiménez, Ana Fontalba-Romero, Dolores Garcia-Medina, Julian Palomino-Doza, David de Gonzalo-Calvo, Marcos Cicerchia, Joel Salazar-Mendiguchia, Clara Salas, Sabine Pankuweit, Thomas Morris Hey, Jens Mogensen, Paul J. Barton, Philippe Charron, Perry Elliott, Pablo Garcia-Pavia, Hans Eiskjær, Roberto Barriales, Xusto Fernández Fernández, Lorenzo Monserrat, Maria Victoria Mogollón, Tomás Ripoll, Pascale Richard, Julian Palomino Doza, Ana Fontalba, Luis Alonso-Pulpón, Marta Cobo-Marcos, Manuel Gómez-Bueno, Esther González-López, Aitor Hernández-Hernández, Francisco José Hernández-Pérez, Ángela López-Sainz, Alejandra Restrepo-Córdoba, Javier Segovia-Cubero, Rocio Toro, Félix Rosa Longobardo, Javier Limeres, Jose Manuel Garcia-Pinilla, Miguel A. López-Garrido, Juan Jiménez-Jaimez, Diego Rangel Sousa, Maria Luisa Peña, Thomas Morris-Hey, Stuart A. Cook, William Midwinter, Angharad M. Roberts, James S. Ware, Roddy Walsh, Perry M. Elliott, Luis Rocha-Lopes, Konstantinos Savvatis, Petros Syrris, Ewa Michalak, Rafal Ploski, Malgorzata Sobieszczanska-Malek, Annette Baas, Dennis Dooijes, Instituto de Salud Carlos III, Fundación Progreso y Salud, Ministerio de Economía y Competitividad (España), Mutual Médica, European Research Area Network on Cardiovascular Diseases, British Heart Foundation, Wellcome Trust, National Institute for Health Research (UK), Danish Heart Foundation, University of Southern Denmark, Odense University Hospital, Competence Network for Heart Failure (Germany), Dutch Heart Foundation, European Commission, Health In Code, Department of Health, and Cardiology
- Subjects
0301 basic medicine ,Male ,medicine.medical_treatment ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Cohort Studies ,Electrocardiography ,0302 clinical medicine ,Interquartile range ,genetics ,Heart transplantation ,BAG3 ,Incidence (epidemiology) ,Dilated cardiomyopathy ,Middle Aged ,1117 Public Health And Health Services ,Cohort ,Cardiology ,cardiovascular system ,Female ,Cardiology and Cardiovascular Medicine ,Adult ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,Adolescent ,1102 Cardiovascular Medicine And Haematology ,Article ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Journal Article ,Humans ,Animals ,cardiovascular diseases ,Adaptor Proteins, Signal Transducing ,Heart Failure ,business.industry ,medicine.disease ,dilated cardiomyopathy ,030104 developmental biology ,Cardiovascular System & Hematology ,Ventricular assist device ,Heart failure ,Mutation ,Cats ,prognosis ,business ,Apoptosis Regulatory Proteins ,Follow-Up Studies - Abstract
[Background] The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood. [Objectives] This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. [Methods] The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. [Results] At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. [Conclusions] DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations., This work was supported by grants from the following institutions: Instituto de Salud Carlos III (ISCIII) (PI14/ 0967, PI15/01551, AC16/0014), CIBERCV (CB16/11/00403), Progreso and Salud Foundation (Junta de Andalucia) (PI-0011/201), Ministry of Economy, Industry and Competitiveness (IJCI-2016-29393), Mutual Medical (Research Award 2017), ERA-CVD Joint Transnational Call 2016 (Genprovic), British Heart Foundation (SP/10/10/28431), Wellcome Trust (107469/Z/15/), NIHR Royal Brompton Cardiovascular Biomedical Research Unit, NIHR Imperial Biomedical Research Center, Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, U.K. (HICF-R6-373), Danish Heart Foundation (16-R107-A6617), University of Southern Denmark, the Region of Southern Denmark, Odense University Hospital, German Competence Network Heart Failure, (TP9, FKZ 01GI0205), DETECTIN-HF project (ERA-CVD framework), and PROMEX Charitable Foundation. UCL Hospitals NIHR Biomedical Research Center and Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2015-12 eDETECT and CVON2014-40 DOSIS. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de IþDþI 2013-2016 – European Regional Development Fund (FEDER) “A way of making Europe.” The Hospital Universitario Puerta de Hierro Majadahonda, Hôpital PitiéSalpêtrière, and Saint Bartholomews’ Hospital are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). Drs. Ochoa, Cicerchia, and Salazar-Mendiguchia are employees of Health In Code.
- Published
- 2018
50. Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3–Induced Myocarditis
- Author
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Sophie Van Linthout, Dirk Lassner, Kathleen Pappritz, Burkert Pieske, Carsten Tschöpe, Uwe Kühl, Irene Müller, Thomas Vogl, Konstantinos Savvatis, Kapka Miteva, Patrick Most, and David Rohde
- Subjects
Male ,0301 basic medicine ,Chemokine ,viruses ,Chemokine CXCL2 ,Receptor for Advanced Glycation End Products ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,Mice ,0302 clinical medicine ,Myocytes, Cardiac ,Mice, Knockout ,Gene knockdown ,biology ,virus diseases ,Middle Aged ,musculoskeletal system ,Enterovirus B, Human ,Myocarditis ,Neutrophil Infiltration ,Host-Pathogen Interactions ,Knockout mouse ,cardiovascular system ,Female ,RNA Interference ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,Adult ,Coxsackievirus Infections ,Inflammation ,Transfection ,S100A9 ,S100A8 ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,Calgranulin B ,Humans ,Calgranulin A ,RNA, Messenger ,cardiovascular diseases ,business.industry ,Macrophages ,medicine.disease ,Fibrosis ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,RAW 264.7 Cells ,030104 developmental biology ,Case-Control Studies ,Immunology ,biology.protein ,business - Abstract
Background: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)–induced myocarditis. Methods and Results: S100A8 and S100A9 mRNA expression was 13.0-fold ( P =0.012) and 5.1-fold ( P =0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. Conclusions: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
- Published
- 2017
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