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1. Myocardial Fibrosis and Inflammation by CMR Predict Cardiovascular Outcome in People Living With HIV

Author: Gundolf Schuettfort, Monika Gawor, H Zhou, Philipp de Leuw, Timo Wolf, Eleftherios Vidalakis, Moritz H. Albrecht, Thomas J. Vogl, Felicitas Escher, Luca Arcari, Hafisyatul Zainal, Gerrit Kann, M Vasquez, Valentina O. Puntmann, Eike Nagel, Christophe T. Arendt, Andreas M. Zeiher, Christoph Stephan, Daniel Froadinadl, Michael Kolentinis, and Annette Haberl
Subjects: Male, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Human immunodeficiency virus (HIV), HIV Infections, Inflammation, 030204 cardiovascular system & hematology, medicine.disease_cause, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Longitudinal Studies, Cardiac imaging, business.industry, Stroke Volume, Middle Aged, Fibrosis, Cardiology, Female, Myocardial fibrosis, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Cardiac magnetic resonance
Abstract: The goal of this study was to examine prognostic relationships between cardiac imaging measures and cardiovascular outcome in people living with human immunodeficiency virus (HIV) (PLWH) on highly active antiretroviral therapy (HAART).PLWH have a higher prevalence of cardiovascular disease and heart failure (HF) compared with the noninfected population. The pathophysiological drivers of myocardial dysfunction and worse cardiovascular outcome in HIV remain poorly understood.This prospective observational longitudinal study included consecutive PLWH on long-term HAART undergoing cardiac magnetic resonance (CMR) examination for assessment of myocardial volumes and function, T1 and T2 mapping, perfusion, and scar. Time-to-event analysis was performed from the index CMR examination to the first single event per patient. The primary endpoint was an adjudicated adverse cardiovascular event (cardiovascular mortality, nonfatal acute coronary syndrome, an appropriate device discharge, or a documented HF hospitalization).A total of 156 participants (62% male; age [median, interquartile range]: 50 years [42 to 57 years]) were included. During a median follow-up of 13 months (9 to 19 months), 24 events were observed (4 HF deaths, 1 sudden cardiac death, 2 nonfatal acute myocardial infarction, 1 appropriate device discharge, and 16 HF hospitalizations). Patients with events had higher native T1 (median [interquartile range]: 1,149 ms [1,115 to 1,163 ms] vs. 1,110 ms [1,075 to 1,138 ms]); native T2 (40 ms [38 to 41 ms] vs. 37 ms [36 to 39 ms]); left ventricular (LV) mass index (65 g/mOur findings reveal important prognostic associations of diffuse myocardial fibrosis and LV remodeling in PLWH. These results may support development of personalized approaches to screening and early intervention to reduce the burden of HF in PLWH (International T1 Multicenter Outcome Study; NCT03749343).
Published: 2021

2. Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure

Author: Sebastian Cremer, Mariuca Vasa-Nicotera, Stefanie Dimmeler, Bianca Schuhmacher, Maximillian Merten, Wesley Abplanalp, Andreas M. Zeiher, Jedrzej Hoffmann, Michael A. Rieger, and David John
Subjects: Male, 0301 basic medicine, THP-1 Cells, Physiology, T-Lymphocytes, Inflammation, Disease, 030204 cardiovascular system & hematology, Monocytes, Article, DNA Methyltransferase 3A, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Paracrine Communication, Cell Adhesion, Human Umbilical Vein Endothelial Cells, medicine, Humans, DNA (Cytosine-5-)-Methyltransferases, RNA-Seq, Immunogenetic Phenomena, Aged, Heart Failure, business.industry, Monocyte, Incidence (epidemiology), Interleukin, Middle Aged, medicine.disease, Coculture Techniques, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Heart failure, Chronic Disease, Mutation, Immunology, Female, Clonal Hematopoiesis, Inflammation Mediators, Single-Cell Analysis, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Rationale: Clonal hematopoiesis driven by mutations of DNMT3A (DNA methyltransferase 3a) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A clonal hematopoiesis–driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Objective: To define subsets of immune cells mediating inflammation in humans using single-cell RNA sequencing. Methods and Results: Transcriptomic profiles of peripheral blood mononuclear cells were analyzed in n=6 patients with HF harboring DNMT3A clonal hematopoiesis–driver mutations and n=4 patients with HF and no DNMT3A mutations by single-cell RNA sequencing. Monocytes of patients with HF carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared with monocytes derived from patients with HF without DNMT3A mutations. Among the specific upregulated genes were the prototypic inflammatory IL (interleukin) IL1B (interleukin 1B), IL6, IL8 , the inflammasome NLRP3 , and the macrophage inflammatory proteins CCL3 and CCL4 as well as resistin, which augments monocyte-endothelial adhesion. Silencing of DNMT3A in monocytes induced a paracrine proinflammatory activation and increased adhesion to endothelial cells. Furthermore, the classical monocyte subset of DNMT3A mutation carriers showed increased expression of T-cell stimulating immunoglobulin superfamily members CD300LB , CD83 , SIGLEC12 , as well as the CD2 ligand and cell adhesion molecule CD58 , all of which may be involved in monocyte–T-cell interactions. DNMT3A mutation carriers were further characterized by increased expression of the T-cell alpha receptor constant chain and changes in T helper cell 1, T helper cell 2, T helper cell 17, CD8+ effector, CD4+ memory, and regulatory T-cell–specific signatures. Conclusions: This study demonstrates that circulating monocytes and T cells of patients with HF harboring clonal hematopoiesis–driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic HF.
Published: 2021

3. Efficiency and Target Derepression of Anti-miR-92a: Results of a First in Human Study

Author: Guillaume Allée, Isabelle Paty, Stefanie Dimmeler, Andreas M. Zeiher, Helene Darville, Willy Gosgnach, Ariane Fischer, Wesley Abplanalp, Rusty Montgomery, Linda Pestano, Francoise Fougerousse, and David John
Subjects: Adult, Male, 0301 basic medicine, Integrins, Adolescent, Oligonucleotides, Biology, Biochemistry, Extracellular Vesicles, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, microRNA, Genetics, Humans, Cell Lineage, Locked nucleic acid, Molecular Biology, Derepression, Therapeutic strategy, Wound Healing, Membrane Glycoproteins, Antagomirs, First in human, Middle Aged, Oligonucleotides, Antisense, Receptors, Complement, Platelet Endothelial Cell Adhesion Molecule-1, MicroRNAs, 030104 developmental biology, Single cell sequencing, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Antisense oligonucleotides, Cancer research, Molecular Medicine, Female
Abstract: MicroRNA (miRNA) inhibition is a promising therapeutic strategy in several disease indications. MRG-110 is a locked nucleic acid-based antisense oligonucleotide that targets miR-92a-3p and experimentally was shown to have documented therapeutic effects on cardiovascular disease and wound healing. To gain first insights into the activity of anti-miR-92a in humans, we investigated miR-92a-3p expression in several blood compartments and assessed the effect of MRG-110 on target derepression. Healthy adults were randomly assigned (5:2) to receive a single intravenous dose of MRG-110 or placebo in one of seven sequential ascending intravenous dose cohorts ranging from 0.01 to 1.5 mg/kg body weight. MiR-92a-3p whole blood levels were time and dose dependently decreased with half-maximal inhibition of 0.27 and 0.31 mg/kg at 24 and 72 h after dosing, respectively. In the high-dose groups,95% inhibition was detected at 24-72 h postinfusion and significant inhibition was observed for 2 weeks. Similar inhibitory effects were detected in isolated CD31
Published: 2020

4. Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry

Author: Stefan Borgmann, Lukas Tometten, Siegbert Rieg, Kai Wille, Steffen Massberg, Sebastian Cremer, Stefanie Dimmeler, Beate Gruener, Carolin Jakob, Andreas M. Zeiher, Lisa Pilgram, Simon Weidlich, Alexander Berkowitsch, Annika Y. Classen, and LEOSS study group
Subjects: Adult, Male, medicine.medical_specialty, Multivariate analysis, Coronavirus disease 2019 (COVID-19), Adverse outcomes, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, ddc:610, Registries, Mortality, Aged, Inflammation, Aged, 80 and over, Original Paper, Coagulation, biology, business.industry, Clinical course, COVID-19, Thrombosis, General Medicine, Middle Aged, Troponin, Cardiovascular Diseases, Myocardial injury, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Aims SARS-CoV-2 infection is associated with adverse outcomes in patients with cardiovascular disease. Here, we analyzed whether specific biomarkers predict the clinical course of COVID-19 in patients with cardiovascular comorbidities. Methods and results We enrolled 2147 patients with SARS-CoV-2 infection which were included in the Lean European Open Survey on SARS-CoV‑2 (LEOSS)-registry from March to June 2020. Clinical data and laboratory values were collected and compared between patients with and without cardiovascular comorbidities in different clinical stages of the disease. Predictors for mortality were calculated using multivariate regression analysis. We show that patients with cardiovascular comorbidities display significantly higher markers of myocardial injury and thrombo-inflammatory activation already in the uncomplicated phase of COVID-19. In multivariate analysis, elevated levels of troponin [OR 1.54; (95% CI 1.22–1.96), p p p Conclusion Patients with cardiovascular comorbidities show elevated markers of thrombo-inflammatory activation and myocardial injury, which predict mortality, already in the uncomplicated phase of COVID-19. Starting targeted anti-inflammatory therapy and aggressive anticoagulation already in the uncomplicated phase of the disease might improve outcomes after SARS-CoV-2 infection in patients with cardiovascular comorbidities. Graphic abstract Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry
Published: 2020

5. Percutaneous coronary intervention for chronic total occlusion in octogenarians: a propensity score study

Author: Recha R. L. Blessing, Majid Ahoopai, Martin Geyer, Moritz Brandt, Andreas M. Zeiher, Mariuca Vasa-Nicotera, Thomas Münzel, Philip Wenzel, Tommaso Gori, and Zisis Dimitriadis
Subjects: Adult, Aged, 80 and over, Male, Octogenarians, Multidisciplinary, Age Factors, 610 Medizin, Middle Aged, Percutaneous Coronary Intervention, Postoperative Complications, Treatment Outcome, Coronary Occlusion, 610 Medical sciences, Feasibility Studies, Humans, Female, Propensity Score, Aged, Follow-Up Studies
Abstract: Feasibility and efficacy of complex percutaneous coronary intervention (PCI) in the elderly, a more frail population due to more comorbidities is incompletely understood. We therefore set out to compare success and complication rate of PCI for chronic total occlusion (CTO) in octogenarians, in comparison to non-octogenarians. Data from 267 patients (58 patients over 80 years of age and 209 under 80 years of age) who had undergone CTO PCI were analyzed. To compare the results we calculated the propensity score and used inverse probability of treatment weighting. We evaluated demographic, clinical, angiographic, and periprocedural information. The median age of the total collective was 68 (31–90) years (octogenarian collective 82 (80–90) years vs non-octogenarians 65 (31–79) years). We observed a high success rate in both collectives (82.8% vs 90.4%, p = 0.10) and no difference in periprocedural complications or complications in the follow-up period. In our collective restenosis rate at follow-up was comparable to the propensity sore weighted population (11.3% vs 16.3%, p = 0.9). Our results show that CTO PCI in older patients is safe and feasible with comparable in-hospital and follow-up complication rates compared to a younger patient population.
Published: 2022

6. A Novel Method to Predict Mortality and Length of Stay after Transfemoral Transcatheter Aortic Valve Implantation

Author: Maria Zisiopoulou, Alexander Berkowitsch, Philipp Seppelt, Andreas M. Zeiher, and Mariuca Vasa-Nicotera
Subjects: Aged, 80 and over, Male, Medicine (General), biomarkers, personalized, aortic valve stenosis, prediction, Length of Stay, outcomes, Risk Assessment, Article, TAVI, Transcatheter Aortic Valve Replacement, R5-920, Treatment Outcome, Risk Factors, Aortic Valve, Humans, Female, KCCQ, Prospective Studies, EQ5D5L
Abstract: Background and Objectives: We tested if a novel combination of predictors could improve the accuracy of outcome prediction after transfemoral transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective study recruited 169 participants (49% female; median age 81 years). The primary endpoint was midterm mortality; secondary endpoints were acute Valve Academic Research Consortium (VARC)-3 complication rate and post-TAVI in-hospital length of stay (LoS). EuroSCORE II (ESII), comorbidities (e.g., coronary artery disease), eGFR (estimated glomerular filtration rate; based on cystatin C), hemoglobin, creatinine, N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels and patient-reported outcome measures (PROMs, namely EuroQol-5-Dimension-5-Levels, EQ5D5L; Kansas City Cardiomyopathy Questionnaire, KCCQ; clinical frailty scale, CFS) at baseline were tested as predictors. Regression (uni- and multi-variate Cox; linear; binary logistic) and receiver operating characteristic (ROC)-curve analysis were applied. Results: Within a median follow-up of 439 (318–585) days, 12 participants died (7.1%). Independent predictors of mortality using multivariate Cox regression were baseline eGFR (p = 0.001) and KCCQ (p = 0.037). Based on these predictors, a Linear Prediction Score (LPS1) was calculated. The LPS1-area under the curve (AUC)-value (0.761) was significantly higher than the ESII-AUC value (0.597; p = 0.035). Independent predictors for LoS > 6 days (the median LoS) were eGFR (p = 0.028), NTproBNP (p = 0.034), and EQ5D5L values (p = 0.002); a respective calculated LPS2 provided an AUC value of 0.677 (p < 0.001). Eighty participants (47.3%) experienced complications. Male sex predicted complications only in the univariate analysis. Conclusions: The combination of KCCQ and eGFR can better predict midterm mortality than ES II alone. Combining eGFR, NTproBNP, and EQ5D5L can reliably predict LoS after TAVI. This novel method improves personalized TAVI risk stratification and hence may help reduce post-TAVI risk.
Published: 2021

7. Long-term cardiac pathology in individuals with mild initial COVID-19 illness

Author: Valentina O. Puntmann, Simon Martin, Anastasia Shchendrygina, Jedrzej Hoffmann, Mame Madjiguène Ka, Eleni Giokoglu, Byambasuren Vanchin, Niels Holm, Argyro Karyou, Gerald S. Laux, Christophe Arendt, Philipp De Leuw, Kai Zacharowski, Yascha Khodamoradi, Maria J. G. T. Vehreschild, Gernot Rohde, Andreas M. Zeiher, Thomas J. Vogl, Carsten Schwenke, and Eike Nagel
Subjects: Male, Heart Diseases, SARS-CoV-2, Myocardium, COVID-19, Contrast Media, Humans, Female, Heart, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.
Published: 2021

8. Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Author: Gregory G. Schwartz, Michael Szarek, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, J. Wouter Jukema, Ulf Landmesser, Patricio López-Jaramillo, Garen Manvelian, Robert Pordy, Michel Scemama, Peter R. Sinnaeve, Harvey D. White, Ph Gabriel Steg, P.h. Gabriel Steg, Deepak L. Bhatt, Robert A. Harrington, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Steen Hvitfeldt Poulsen, Margus Viigimaa, Markku S. Nieminen, Nicolas Danchin, Vakhtang Chumburidze, Nikolaus Marx, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Rody G. Sy, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J. Dalby, José Tuñón, H. Asita de Silva, Emil Hagström, Christian Müller, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean F.P. van Diepen, Matthew D. Wilson, Andrew Tze-Kay Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. Cartasegna, Gustavo A. Paterlini, Ignacio J. Mackinnon, Guillermo D. Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R. Codutti, Horacio O. Jure, Julio O.E. Bono, Adrian D. Hrabar, Julio A. Vallejos, Rodolfo A. Ahuad Guerrero, Federico Novoa, Cristian A. Patocchi, Cesar J. Zaidman, Maria E. Giuliano, Ricardo D. Dran, Marisa L. Vico, Gabriela S. Carnero, Pablo N. Guzman, Juan C. Medrano Allende, Daniela F. Garcia Brasca, Miguel H. Bustamante Labarta, Sebastian Nani, Eduardo D.S. Blumberg, Hugo R. Colombo, Alberto Liberman, Victorino Fuentealba, Hector L. Luciardi, Gabriel D. Waisman, Mario A. Berli, Ruben O. Garcia Duran, Horacio G. Cestari, Hugo A. Luquez, Jorge A. Giordano, Silvia S. Saavedra, Gerardo Zapata, Osvaldo Costamagna, Susana Llois, Jonathon H. Waites, Nicholas Collins, Allan Soward, Chris L.S. Hii, James Shaw, Margaret A. Arstall, John Horowitz, Daniel Ninio, James F. Rogers, David Colquhoun, Romulo E. Oqueli Flores, Philip Roberts-Thomson, Owen Raffel, Sam J. Lehman, Constantine Aroney, Steven G.M. Coverdale, Paul J. Garrahy, Gregory Starmer, Mark Sader, Patrick A. Carroll, Ronald Dick, Robert Zweiker, Uta Hoppe, Kurt Huber, Rudolf Berger, Georg Delle-Karth, Bernhard Frey, Dirk Faes, Kurt Hermans, Bruno Pirenne, Attilio Leone, Etienne Hoffer, Mathias C.M. Vrolix, Luc De Wolf, Bart Wollaert, Marc Castadot, Karl Dujardin, Christophe Beauloye, Geert Vervoort, Harry Striekwold, Carl Convens, John Roosen, Emanuele Barbato, Marc Claeys, Frank Cools, Ibrahim Terzic, Fahir Barakovic, Zlatko Midzic, Belma Pojskic, Emir Fazlibegovic, Azra Durak-Nalbantic, Mehmed Kulić, Dusko Vulic, Adis Muslibegovic, Boris Goronja, Gilmar Reis, Luciano Sousa, Jose C. Nicolau, Flavio E. Giorgeto, Ricardo P. Silva, Lilia Nigro Maia, Rafael Rech, Paulo R.F. Rossi, Maria José A.G. Cerqueira, Norberto Duda, Renato Kalil, Adrian Kormann, José Antonio M. Abrantes, Pedro Pimentel Filho, Ana Priscila Soggia, Mayler O.N. de Santos, Fernando Neuenschwander, Luiz C. Bodanese, Yorghos L. Michalaros, Freddy G. Eliaschewitz, Maria H. Vidotti, Paulo E. Leaes, Roberto V. Botelho, Sergio Kaiser, Euler Roberto F. Fernandes Manenti, Dalton B. Precoma, Jose C. Moura Jorge, Pedro Silva, Jose A. Silveira, Wladmir Saporito, Jose A. Marin Neto, Gilson S. Feitosa, Luiz Eduardo F. Ritt, Juliana A. de Souza, Fernando Costa, Weimar K.S.B. Souza, Helder J.L. Reis, Leandro Machado, José Carlos Aidar Ayoub, Georgi V. Todorov, Fedya P. Nikolov, Elena S. Velcheva, Maria L. Tzekova, Haralambi O. Benov, Stanislav L. Petranov, Haralin S. Tumbev, Nina S. Shehova-Yankova, Dimitar T. Markov, Dimitar H. Raev, Mihail N. Mollov, Kostadin N. Kichukov, Katya A. Ilieva-Pandeva, Raya Ivanova, Maryana Gospodinov, Valentina M. Mincheva, Petar V. Lazov, Bojidar I. Dimov, Manohara Senaratne, James Stone, Jan Kornder, Stephen Pearce, Danielle Dion, Daniel Savard, Yves Pesant, Amritanshu Pandey, Simon Robinson, Gilbert Gosselin, Saul Vizel, Gordon Hoag, Ronald Bourgeois, Anne Morisset, Eric Sabbah, Bruce Sussex, Simon Kouz, Paul MacDonald, Ariel Diaz, Nicolas Michaud, David Fell, Raymond Leung, Tycho Vuurmans, Christopher Lai, Frank Nigro, Richard Davies, Gustavo Nogareda, Ram Vijayaraghavan, John Ducas, Serge Lepage, Shamir Mehta, James Cha, Robert Dupuis, Peter Fong, Sohrab Lutchmedial, Josep Rodes-Cabau, Hussein Fadlallah, David Cleveland, Thao Huynh, Iqbal Bata, Adnan Hameed, Cristian Pincetti, Sergio Potthoff, Juan C. Prieto, Monica Acevedo, Arnoldo Aguirre, Margarita Vejar, Mario Yañez, Guillermo Araneda, Mauricio Fernandez, Luis Perez, Paola Varleta, Fernando Florenzano, Laura Huidobro, Carlos A. Raffo, Claudia Olivares, Leonardo Nahuelpan, Humberto Montecinos, Jiyan Chen, Yugang Dong, Weijian Huang, Jianzhong Wang, Shi'An Huang, Zhuhua Yao, Xiang Li, Lan Cui, Wenhua Lin, Yuemin Sun, Jingfeng Wang, Jianping Li, Xuelian Zhang, Hong Zhu, Dandan Chen, Lan Huang, Shaohong Dong, Guohai Su, Biao Xu, Xi Su, Xiaoshu Cheng, Jinxiu Lin, Wenxia Zong, Huanming Li, Yi Feng, Dingli Xu, Xinchun Yang, Yuannan Ke, Xuefeng Lin, Zheng Zhang, Zeqi Zheng, Zhurong Luo, Yundai Chen, Chunhua Ding, Yi Zhong, Yang Zheng, Xiaodong Li, Daoquan Peng, Shuiping Zhao, Ying Li, Xuebo Liu, Meng Wei, Shaowen Liu, Yihua Yu, Baiming Qu, Weihong Jiang, Yujie Zhou, Xingsheng Zhao, Zuyi Yuan, Ying Guo, Xiping Xu, Xubo Shi, Junbo Ge, Guosheng Fu, Feng Bai, Weiyi Fang, Xiling Shou, Xiangjun Yang, Jian'An Wang, Meixiang Xiang, Yingxian Sun, Qinghua Lu, Ruiyan Zhang, Jianhua Zhu, Yizhou Xu, Zhongcai Fan, Tianchang Li, Chun Wu, Nicolas Jaramillo, Gregorio Sanchez Vallejo, Diana C. Luna Botia, Rodrigo Botero Lopez, Dora I. Molina De Salazar, Alberto J. Cadena Bonfanti, Carlos Cotes Aroca, Juan Diego Higuera, Marco Blanquicett, Sandra I. Barrera Silva, Henry J. Garcia Lozada, Julian A. Coronel Arroyo, Jose L. Accini Mendoza, Ricardo L. Fernandez Ruiz, Alvaro M. Quintero Ossa, Fernando G. Manzur Jatin, Aristides Sotomayor Herazo, Jeffrey Castellanos Parada, Rafael Suarez Arambula, Miguel A. Urina Triana, Angela M. Fernandez Trujillo, Maja Strozzi, Siniša Car, Melita Jerić, Davor Miličić, Martina Lovrić Benčić, Hrvoje Pintarić, Đeiti Prvulović, Jozica Šikić, Viktor Peršić, Dean Mileta, Kresimir Štambuk, Zdravko Babić, Vjekoslav Tomulic, Josip Lukenda, Stanka Mejic-Krstulovic, Boris Starcevic, Jindrich Spinar, David Horak, Zdenek Velicka, Josef Stasek, David Alan, Vilma Machova, Ales Linhart, Vojtech Novotny, Vladimir Kaucak, Richard Rokyta, Robert Naplava, Zdenek Coufal, Vera Adamkova, Ivo Podpera, Jiri Zizka, Zuzana Motovska, Ivana Marusincova, Premysl Svab, Petr Heinc, Jiri Kuchar, Petr Povolny, Jiri Matuska, Steen H. Poulsen, Bent Raungaard, Peter Clemmensen, Lia E. Bang, Ole May, Morten Bøttcher, Jens D. Hove, Lars Frost, Gunnar Gislason, John Larsen, Peter Betton Johansen, Flemming Hald, Peter Johansen, Jørgen Jeppesen, Tonny Nielsen, Kjeld S. Kristensen, Piotr Maria Walichiewicz, Jens D. Lomholdt, Ib C. Klausen, Peter Kaiser Nielsen, Flemming Davidsen, Lars Videbaek, Mai Soots, Veiko Vahula, Anu Hedman, Üllar Soopõld, Kaja Märtsin, Tiina Jurgenson, Arved Kristjan, Heikki Huikuri, Juhani Airaksinen Pierre Coste, Emile Ferrari, Olivier Morel, Gilles Montalescot, Jacques Machecourt, Gilles Barone-Rochette, Jacques Mansourati, Yves Cottin, Florence Leclercq, Abdelkader Belhassane, Nicolas Delarche, Franck Boccara, Franck Paganelli, Jérôme Clerc, Francois Schiele, Victor Aboyans, Vincent Probst, Jacques Berland, Thierry Lefèvre, Bernard Citron, Irakli Khintibidze, Tamaz Shaburishvili, Zurab Pagava, Ramaz Ghlonti, Zaza Lominadze, George Khabeishvili, Rayyan Hemetsberger, Kemala Edward, Ursula Rauch-Kröhnert, Matthias Stratmann, Karl-Friedrich Appel, Ekkehard Schmidt, Heyder Omran, Christoph Stellbrink, Thomas Dorsel, Emmanouil Lianopoulos, Hans Friedrich Vöhringer, Roger Marx, Andreas Zirlik, Detlev Schellenberg, Thomas Heitzer, Ulrich Laufs, Christian Werner, Stephan Gielen, Sebastian Nuding, Bernhard Winkelmann, Steffen Behrens, Karsten Sydow, Mahir Karakas, Gregor Simonis, Thomas Muenzel, Nikos Werner, Stefan Leggewie, Dirk Böcker, Rüdiger Braun-Dullaeus, Nicole Toursarkissian, Michael Jeserich, Matthias Weißbrodt, Tim Schaeufele, Joachim Weil, Heinz Völler, Johannes Waltenberger, Mohammed Natour, Susanne Schmitt, Dirk Müller-Wieland, Stephan Steiner, Lothar Heidenreich, Elmar Offers, Uwe Gremmler, Holger Killat, Werner Rieker, Sotiris Patsilinakos, Athanasios Kartalis, Athanassios Manolis, Dimitrios Sionis, Geargios Chachalis, Ioannis Skoumas, Vasilios Athyros, Panagiotis Vardas, Frangkiskos Parthenakis, John Lekakis, Apostolos Hatzitolios, Sergio R. Fausto Ovando, Juan L. Arango Benecke, Edgar R. Rodriguez De Leon, Bryan P.Y. Yan, David C.W. Siu, Tibor Turi, Bela Merkely, Imre Ungi, Geza Lupkovics, Lajos Nagy, András Katona, István Édes, Gábor Müller, Iván Horvath, Tibor Kapin, Zsolt Szigeti, József Faluközy, Mukund Kumbla, Manjinder Sandhu, Sharath Annam, Naveen Reddy Proddutur, Reddy Regella, Rajendra K. Premchand, Ajaykumar Mahajan, Sudhir Pawar, Atul D. Abhyanakar, Prafulla Kerkar, Ravishankar A. Govinda, Abraham Oomman, Dhurjati Sinha, Sachin N. Patil, Dhiman Kahali, Jitendra Sawhney, Abhijeet B. Joshi, Sanjeev Chaudhary, Pankaj Harkut, Santanu Guha, Sanjay Porwal, Srimannarayana Jujjuru, Ramesh B. Pothineni, Minguel R. Monteiro, Aziz Khan, Shamanna S. Iyengar, Jasprakash Singh Grewal, Manoj Chopda, Mahesh C. Fulwani, Aparna Patange, Patil Sachin, Vijay K. Chopra, Naresh K. Goyal, Rituparna Shinde, Gajendra V. Manakshe, Nitin Patki, Sumeet Sethi, Vengatesh Munusamy, Sunil Karnaand Sunil Thanvi, Srilakshmi Adhyapak, Chandrakant Patil, Ulhas Pandurangi, Rishabh Mathur, Jugal Gupta, Suhas Kalashetti, Ajit Bhagwat, Bagirath Raghuraman, Shiv Kumar Yerra, Prasant Bhansali, Rohidas Borse, Patil Rahul, Srihari Das, Vinay Kumar, Jabir Abdullakutty, Shireesh Saathe, Priya Palimkar, Jabir Abdullkutty, Shireesh Sathe, Shaul Atar, Michael Shechter, Morris Mosseri, Yaron Arbel, Chorin Ehud, Havakuk Ofer, Chaim Lotan, Uri Rosenschein, Amos Katz, Yaakov Henkin, Adi Francis, Marc Klutstein, Eugenia Nikolsky, Robert Zukermann, Yoav Turgeman, Majdi Halabi, Alon Marmor, Ran Kornowski, Michael Jonas, Offer Amir, Yonathan Hasin, Yoseph Rozenman, Shmuel Fuchs, Vered Zvi, Osamah Hussein, Dov Gavish, Zvi Vered, Yoseph Caraco, Mazen Elias, Naveh Tov, Efrat Wolfovitz, Michael Lishner, Nizar Elias, Giancarlo Piovaccari, Annamaria De Pellegrin, Raffaella Garbelotto, Gabriele Guardigli, Valgimigli Marco, Giovanni Licciardello, Carla Auguadro, Filippo Scalise, Claudio Cuccia, Alessandro Salvioni, Giuseppe Musumeci, Michelle Senni, Paolo Calabrò, Salvatore Novo, Pompilio Faggiano, Marco Metra, Nicoletta B. De Cesare, Sergio Berti, Claudio Cavallini, Enrico Puccioni, Marcello Galvani, Maurizio Tespili, Piermarco Piatti, Michela Palvarini, Giuseppe De Luca, Roberto Violini, Alessandro De Leo, Zoran Olivari, Pasquale Perrone Filardi, Maurizio Ferratini, Vittorio Racca, Kazuoki Dai, Yuji Shimatani, Haruo Kamiya, Kenji Ando, Yoshihiro Takeda, Yoshihiro Morino, Yoshiki Hata, Kazuo Kimura, Koichi Kishi, Ichiro Michishita, Hiroki Uehara, Toshinori Higashikata, Atsushi Hirayama, Keiji Hirooka, Yasuji Doi, Satoru Sakagami, Shuichi Taguchi, Akihiro Koike, Hiroyuki Fujinaga, Shinji Koba, Ken Kozuma, Tomohiro Kawasaki, Yujiro Ono, Masatoshi Shimizu, Yousuke Katsuda, Atsuyuki Wada, Toshiro Shinke, Junya Ako, Kenshi Fujii, Toshiyuki Takahashi, Tomohiro Sakamoto, Koichi Nakao, Yutaka Furukawa, Hiroshi Sugino, Ritsu Tamura, Toshiaki Mano, Masaaki Uematsu, Noriaki Utsu, Kashima Ito, Takuya Haraguchi, Katsuhiko Sato, Yasunori Ueda, Akira Nishibe, Kazuteru Fujimoto, Motomaru Masutani, Jung Han Yoon, Hack-Lyoung Kim, Hun Sik Park, In-Ho Chae, Moo Hyun Kim, Myung Ho Jeong, Seungwoon Rha, Chongjin Kim, Hae Young Kim, Taekjong Hong, Seung-Jea Tahk, Youngkwon Kim, Arija Busmane, Natalija Pontaga, Aldis Strelnieks, Iveta Mintale, Iveta Sime, Zaneta Petrulioniene, Roma Kavaliauskiene, Ruta Jurgaitiene, Gintare Sakalyte, Rimvydas Slapikas, Sigute Norkiene, Nerijus Misonis, Aleksandras Kibarskis, Raimondas Kubilius, Stojko Bojovski, Nensi Lozance, Aleksandar Kjovkaroski, Snezana Doncovska, Tiong Kiam Ong, Sazzli Kasim, Oteh Maskon, Balachandran Kandasamy, Houng B. Liew, Wan Mohd Izani Wan Mohamed, Armando García Castillo, Jorge Carrillo Calvillo, Pedro Fajardo Campos, Juan Carlos Núñez Fragoso, Edmundo Alfredo Bayram Llamas, Marco Antonio Alcocer Gamba, Jaime Carranza Madrigal, Luis Gerardo González Salas, Enrique López Rosas, Belinda González Díaz, Eduardo Salcido Vázquez, Alfredo Nacoud Ackar, Guillermo Antonio Llamas Esperón, Carlos Rodolfo Martínez Sánchez, María Guerrero De Leon, Rodrigo Suarez Otero, Guillermo Fanghänel Salmón, Jesús Antonio Pérez Ríos, José Angel Garza Ruíz, Robert W. Breedveld, Margriet Feenema-Aardema, Alida Borger-Van Der Burg, Pieter A.M. Hoogslag, Harry Suryapranata, Antonius Oomen, Paulus Van Haelst, Margriet Feenema-Aradema, Jacobijne J. Wiersma, Dirk Basart, Ruud M.A. Van Der Wal, Peter Zwart, Pascalle Monraats, Henricus Van Kesteren, Ioannis Karalis, Johan Jukema, Gerardus J.E. Verdel, Bart R.G. Brueren, Roland PTh Troquay, Eric P. Viergever, Nadea Y.Y. Al-Windy, Gerard L. Bartels, Jan H. Cornel, Walter R.M. 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Bravo Mannucci, Javier Heredia Landeo, Nassip C. Llerena Navarro, Yudy M. Roldan Concha, Víctor E. Rodriguez Chavez, Henry A. Anchante Hernandez, Carlos A. Zea Nunez, Walter Mogrovejo Ramos, Arthur Ferrolino, Rosa Allyn G. Sy, Louie Tirador, Generoso Matiga, Raul Martin Coching, Alisa Bernan, Gregorio Rogelio, Dante D. Morales, Edgar Tan, Dennis Jose Sulit, Adrian Wlodarczak, Krystyna Jaworska, Grzegorz Skonieczny, Lidia Pawlowicz, Pawel Wojewoda, Benita Busz-Papiez, Janusz Bednarski, Aleksander Goch, Pawel Staneta, Elzbieta Dulak, Krzysztof Saminski, Wlodzimierz Krasowski, Wanda Sudnik, Aleksander Zurakowski, Marcin Skorski, Roman Lysek, Beata Miklaszewicz, Jacek Kubica, Jan Andrzej Lipko, Edyta Kostarska-Srokosz, Marek Piepiorka, Anna Drzewiecka, Ryszard Sciborski, Arkadiusz Stasiewski, Tomasz Blicharski, Leszek Bystryk, Michal Szpajer, Marek Korol, Tomasz Czerski, Ewa Mirek-Bryniarska, Jacek Gniot, Andrzej Lubinski, Jerzy Gorny, Edward Franek, Grzegorz Raczak, Hanna Szwed, Pedro Monteiro, Jose Mesquita Bastos, Helder H. Pereira, Dinis Martins, Filipe Seixo, Carlos Mendonça, Ana Botelho, Francisca Caetano, Bogdan Minescu, Octavian Istratoaie, Dan N. Tesloianu, Gabriel Cristian, Silviu Dumitrescu, Cristian G.C. Podoleanu, Mircea C.A. Constantinescu, Cristina M. Bengus, Constantin Militaru, Doina Rosu, Irinel R. Parepa, Adrian V. Matei, Tom M. Alexandru, Mihaela Malis, Ioan Coman, Rodica Stanescu-Cioranu, Doina Dimulescu, Yury Shvarts, Olga Orlikova, Zhanna Kobalava, Olga L. Barbarash, Valentin Markov, Nadezhda Lyamina, Alexander Gordienko, Konstantin Zrazhevsky, Alexander Y. Vishnevsky, Victor Gurevich, Raisa Stryuk, Nikita V. Lomakin, Igor Bokarev, Tatiana Khlevchuk, Sergey Shalaev, Larisa Khaisheva, Petr Chizhov, Inna Viktorova, Natalya Osokina, Vladimir Shchekotov, Evgenia Akatova, Galina Chumakova, Igor Libov, Mikhail I. Voevoda, Tatyana V. Tretyakova, Evgeny Baranov, Sergey Shustov, Sergey Yakushin, Ivan Gordeev, Niiaz Khasanov, Olga Reshetko, Tatiana Sotnikova, Olga Molchanova, Konstantin Nikolaev, Liudmila Gapon, Elena Baranova, Zaur Shogenov, Elena Kosmachova, Yuriy Karpov, Anton Povzun, Liudmila Egorova, Vadim V. Tyrenko, Igor G. Ivanov, Masterov Ilya, Sergey Kanorsky, Dragan Simic, Nikola Ivanovic, Goran Davidovic, Nebojsa Tasic, Milika R. Asanin, Stevo Stojic, Svetlana R. Apostolovic, Stevan Ilic, Biljana Putnikovic Tosic, Aleksandar Stankovic, Aleksandra Arandjelovic, Slavica Radovanovic, Branislava Todic, Jovan Balinovac, Dragan V. Dincic, Petar Seferovic, Ana Karadzic, Slobodan Dodic, Sinisa Dimkovic, Tamara Jakimov, Kian-Keong Poh, Hean Yee Ong, Justin Tang I-Shing, Karol Micko, Jan Nociar, Daniel Pella, Peter Fulop, Marian Hranai, Juraj Palka, Juraj Mazur, Ivan Majercák, Andrej Dzupina, František Fazekas, Jozef Gonsorcik, Viliam Bugan, Juraj Selecky, Gabriel Kamensky, Jaroslava Strbova, Rudolf Smik, Andrej Dukat, Peter Olexa, Ivan Žuran, Janez Poklukar, Nataša Černič Šuligoj, Matija Cevc, Henry P. Cyster, Naresh Ranjith, Clive Corbett, Junaid Bayat, Ellen Makoali Makotoko, Hendrik du Toit Theron, Ilse E. Kapp, Matthys M. de V Basson, Hanlie Lottering, Dina Van Aswegen, Louis J. Van Zyl, Peter J. Sebastian, Thayabran Pillay, Jan A. Saaiman, Patrick J. Commerford, Soraya Cassimjee, Garda Riaz, Iftikhar O. Ebrahim, Mahomed Sarvan, Joseph H. Mynhardt, Helmuth Reuter, Rajendran Moodley, Manuel Vida, Angel R. Cequier Fillat, Vicente Bodí Peris, Francisco Fuentes Jimenez, Francisco Marín, Jose M. Cruz Fernández, Rafael Jesus Hidalgo Urbano, Blas Gil-Extremera, Pablo Toledo, Fernando Worner Diz, David Garcia-Dorado, Andres Iñiguez, José Tuñón Fernández, Jose R. Gonzalez-Juanatey, Javier Fernandez Portales, Fernando Civeira Murillo, Laia Matas Pericas, Jose Luis Zamorano, Manuel De Mora Martin, Jordi Bruguera Cortada, Joaquin J. Alonso Martin, Jose Maria Serrano Antolin, José R. De Berrazueta Fernández, José Antonio Vázquez de Prada, Jose Francisco Díaz Fernández, José Alberto García Lledó, Juan Cosín Sales, Javier Botas Rodriguez, Gabriel Gusi Tragant, Amparo Benedicto, Carlos Gonzalez-Juanatey, Mercedes Camprubí Potau, Ignacio Plaza Perez, César Morís De La Tassa, Pablo Loma-Osorio Rincon, Javier Balaguer Recena, Juan M. Escudier, Antonio Coca Payeras, Norberto Alonso Orcajo, Pedro Valdivielso, Godwin Constantine, Ruvaiz Haniffa, Nirmali Tissera, Stanley Amarasekera, Chandrike Ponnamperuma, Nimali Fernando, Kaputella Fernando, Jayanthimala Jayawardena, Santharaj Wijeyasingam, Gotabhaya Ranasinghe, Ruvan Ekanayaka, Sepalika Mendis, Vajira Senaratne, Gnanamoorthy Mayurathan, Ajantha Rajapaksha, Thilak Sirisena, Jagath I. Herath, Naomali Amarasena, Stefan Berglund, Gundars Rasmanis, Ola Vedin, Nils Witt, Georgios Mourtzinis, Peter Nicol, Ole Hansen, Stefano Romeo, Steen Agergaard Jensen, Ingemar Torstensson, Ulf Ahremark, Torbjörn Sundelin, Tiziano Moccetti, Francois Mach, Ronald Binde, Oliver Gämperli, Wei-Chuan Tsai, Kwo-Chang Ueng, Wen-Ter Lai, Ming-En Liu, Juey-Jen Hwang, Wei-Hsian Yin, I-Chang Hsieh, Ming-Jer Hsieh, Wei Hsiang Lin, Jen-Yuan Kuo, Tsuei-Yuan Huang, Chih-Yuan Fang, Pinij Kaewsuwanna, Wasant Soonfuang, Woravut Jintapakorn, Apichard Sukonthasarn, Nattawut Wongpraparut, Krisada Sastravaha, Nakarin Sansanayudh, Wirash Kehasukcharoen, Dilok Piyayotai, Paiboon Chotnoparatpat, Ahmet Camsari, Hakan Kultursay, Bulent Mutlu, Murat Ersanli, Mustafa Demirtas, Cevat Kirma, Ertan Ural, Lale Koldas, Oleksandr Karpenko, Alexander Prokhorov, Ihor Vakaluyk, Halyna Myshanych, Dmytro Reshotko, Valeriy Batushkin, Leonid Rudenko, Ihor Kovalskyi, Mykola Kushnir, Vira Tseluyko, Yuriy Mostovoy, Mykola Stanislavchuk, Yulian Kyiak, Yuriy Karpenko, Yaroslav Malynovsky, Andriy Klantsa, Oles Kutniy, Ekaterina Amosova, Viktor Tashchuk, Oleh Leshchuk, Mykola Rishko, Mykola Kopytsya, Andriy Yagensky, Mykola Vatutin, Andriy Bagriy, Olga M. Barna, Olexiy Ushakov, Georgiy Dzyak, Borys Goloborodko, Anatolii Rudenko, Volodymyr Zheleznyy, Jasper Trevelyan, Azfar Zaman, Kaeng Lee, Andrew Moriarty, Rajesh K. Aggarwal, Piers Clifford, Yuk-Ki Wong, Syed M.R. Iqbal, Eduardas Subkovas, Denise Braganza, David Sarkar, Robert Storey, Huw Griffiths, Sam Mcclure, Rangasamy Muthusamy, Simon Smith, John Kurian, Terry Levy, Craig Barr, Honer Kadr, Robert Gerber, Audrius Simaitis, Handrean Soran, Anthony Mathur, Adrian Brodison, Mohammad Ayaz, Muhammad Cheema, Richard Oliver, Simon Thackray, Telal Mudawi, Gohar Rahman, Ayyaz Sultan, Timothy Reynolds, David Sharman, null david Sprigings, Rob Butler, Peter Wilkinson, Gregory Y.H. Lip, Julian Halcox, Sean Gallagher, Nicholas Ossei-Gerning, Gil Vardi, Duccio Baldari, David Brabham, Charles Treasure, Charles Dahl, Bruce Palmer, Alan Wiseman, Abul Khan, Sanjeev Puri, Ann Elizabeth Mohart, Carlos Ince, Enrique Flores, Scott Wright, Shi-Chi Cheng, Michael Rosenberg, William Rogers, Edward Kosinski, Les Forgosh, Jonathan Waltman, Misal Khan, Mohammad Shoukfeh, Georges Dagher, Patrick Cambier, Ira Lieber, Priya Kumar, Cara East, Perry Krichmar, Mian Hasan, Lindsey White, Thomas Knickelbine, Thomas Haldis, Eve Gillespie, Thomas Amidon, David Suh, Imran Arif, Mouhamad Abdallah, Faiq Akhter, Eric Carlson, Michael D'Urso, Fadi El-Ahdab, William Nelson, Katie Moriarty, Barry Harris, Steven Cohen, Luther Carter, Daniel Doty, Kenneth Sabatino, Tariq Haddad, Amir Malik, Sunder Rao, Angel Mulkay, Ion Jovin, Kim Klancke, Vinay Malhotra, Sai K. Devarapalli, Michael Koren, Harish Chandna, George Dodds, Tauqir Goraya, James Bengston, Matthew Janik, Joseph Moran, Andrew Sumner, John Kobayashi, William Davis, Shahram Yazdani, John Pasquini, Maitreya Thakkar, Amarnath Vedere, Wayne Leimbach, James Rider, Sarah fenton, Narendra Singh, Anil V. Shah, Denise Janosik, Carl Pepine, Brett Berman, Joseph Gelormini, Christopher Daniels, Kerensky Richard, Friederike Keating, Nicholas I. Kondo, Sanjay Shetty, Howard Levite, Winfried Waider, Theodore Takata, Mazen Abu-Fadel, Vipul Shah, Rahul Aggarwal, Mark Izzo, Anil Kumar, Brack Hattler, Rose Do, Chad Link, Anna Bortnick, George Kinzfogl, Arnold Ghitis, John Larry, Edward Teufel, Peter Kuhlman, Brent Mclaurin, Wenwu Zhang, Stephen Thew, Jalal Abbas, Matthew White, Othman Islam, Sumeet Subherwal, Nandkishore Ranadive, Babak Vakili, Christian Gring, David Henderson, Timothy Schuchard, Naim Farhat, Geoffrey Kline, Sharan Mahal, Jack Whitaker, Shawn Speirs, Rolf Andersen, Nizar Daboul, Phillip Horwitz, Firas Zahr, George Ponce, Zubair Jafar, Joseph Mcgarvey, Vipul Panchal, Stephen Voyce, Thomas Blok, William Sheldon, Masoud M. Azizad, Carsten Schmalfuss, Mark Picone, Robert Pederson, William Herzog, Keith Friedman, Jason Lindsey, Rosemary Nowins, Eichenlaub Timothy, Parilak Leonard, Norman Lepor, Mahfouz El Shahawy, Howard Weintraub, Anand Irimpen, Alvaro Alonso, Wade May, Daniels Christopher, Thomas Galski, Alan Chu, Freny Mody, Ebrahimi Ramin, Zachary Hodes, Joseph Rossi, Gregory Rose, James Fairlamb, Charles Lambert, Ajit Raisinghani, Antonio Abbate, George Vetrovec, Marilyn King, Charles Carey, Jaime Gerber, Liwa Younis, Hyeun Park, Mladen Vidovich, Thomas Knutson, Dennis Friedman, Fred Chaleff, Arthur Loussararian, Phillip Rozeman, Carey Kimmelstiel, Jeffrey Kuvin, Kevin Silver, Malcolm Foster, Glen Tonnessen, Andrey Espinoza, Mohamadali Amlani, Andreas Wali, Christopher Malozzi, Geert T. Jong, Clara Massey, Keattiyoat Wattanakit, Philip J. O'Donnell, Dinesh Singal, Naseem Jaffrani, Sridhar Banuru, Daniel Fisher, Mark Xenakis, Neal Perlmutter, Ravi Bhagwat, James Strader, Ronald Blonder, Ayim Akyea-Djamson, Ajay Labroo, Kwan Lee, H. John Marais, Edmund Claxton, Robert Weiss, Rohr Kathryn, Martin Berk, Peter Rossi, Parag Joshi, Amit Khera, Ajit S. Khaira, Greg Kumkumian, Steven Lupovitch, Joshua Purow, Stephen Welka, David Hoffman, Stuart Fischer, Eugene Soroka, Donald Eagerton, Samir Pancholy, Michael Ray, Norman Erenrich, Michael Farrar, Stewart Pollock, William J. French, Steve Diamantis, Douglas Guy, Lawrence Gimple, Mark Neustel, Steven Schwartz, Edward Pereira, Seals Albert, Douglas Spriggs, Janet Strain, Suneet Mittal, Anthony Vo, Majed Chane, Jason Hall, Nampalli Vijay, Kapildeo Lotun, F. Martin Lester, Ahed Nahhas, Theodore Pope, Paul Nager, Rakesh Vohra, Mukesh Sharma, Riyaz Bashir, Hinan Ahmed, Michael Berlowitz, Robert Fishberg, Robert Barrucco, Eric Yang, Michael Radin, Daniel Sporn, Dwight Stapleton, Steven Eisenberg, Joel Landzberg, Martin Mcgough, Samir Turk, Michael Schwartz, P. Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M Gilbert, Gopal Chalavarya, Charles Eaton, John F. Schmedtje, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Andrea Pascual, Carla Rovito, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Melanie Verrier, null Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. Colhoun, Michael A. Dempsey, Mark A. McClanahan, Masira, and Laucevičius, Aleksandras
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, Cardiac & Cardiovascular Systems, Randomization, PCSK9 inhibitor, LOW-DENSITY-LIPOPROTEIN, Antibodies, Monoclonal, Humanized, acute coronary syndrom, Placebo, Gastroenterology, lipoprotein(a), Internal medicine, medicine, Humans, Low-density lipoprotein cholesterol, Aged, Alirocumab, RISK, low-density lipoprotein cholesterol, Science & Technology, biology, business.industry, PCSK9, PCSK9 Inhibitors, Hazard ratio, ALIROCUMAB, acute coronary syndrome, Cholesterol, LDL, Lipoprotein(a), Middle Aged, EFFICACY, medicine.disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, SAFETY, Cardiovascular System & Cardiology, biology.protein, Female, lipids (amino acids, peptides, and proteins), STATIN, low-density lipoprotein, cholesterol PCSK9 inhibitor, CORONARY, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine, Mace
Abstract: Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud
Published: 2021

9. Circulating Th17 and Th22 Cells Are Associated With CMR Imaging Biosignatures of Diffuse Myocardial Interstitial Remodeling in Chronic Coronary Artery Disease

Author: Jedrzej Hoffmann, Valentina O. Puntmann, Maria Ludovica Carerj, Alexander Berkowitsch, Karel Fiser, Stefanie Dimmeler, Eike Nagel, Tina Rasper, and Andreas M. Zeiher
Subjects: Male, medicine.medical_specialty, Physiology, Coronary Artery Disease, Immunophenotyping, Coronary artery disease, Predictive Value of Tests, Internal medicine, medicine, myocardium, Humans, Prospective Studies, T-lymphocytes, Aged, Ventricular Remodeling, business.industry, Interleukins, Interleukin-17, T1 mapping, Middle Aged, medicine.disease, Flow Cytometry, Fibrosis, Magnetic Resonance Imaging, Research Letters, Phenotype, Case-Control Studies, Chronic Disease, Cardiology, Th17 Cells, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers
Published: 2020

10. Towards standardized postprocessing of global longitudinal strain by feature tracking – OptiStrain CMR-FT study

Author: Faraz Pathan, Christophe T. Arendt, Valentina O. Puntmann, L. Winau, Robert Heinke, Melanie Le, Eike Nagel, Tommaso D'Angelo, Andreas M. Zeiher, and Thomas J. Vogl
Subjects: Adult, Cardiomyopathy, Dilated, Male, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Standardization, Longitudinal strain, Cardiac magnetic resonance, Myocardial Ischemia, Magnetic Resonance Imaging, Cine, 030204 cardiovascular system & hematology, Ventricular Function, Left, 030218 nuclear medicine & medical imaging, Correlation, Ventricular Dysfunction, Left, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Germany, Image Interpretation, Computer-Assisted, Statistics, Humans, Medicine, In patient, Aged, Angiology, Observer Variation, Reproducibility, business.industry, Myocardial deformation, Reproducibility of Results, Stroke Volume, Middle Aged, Feature tracking, lcsh:RC666-701, Case-Control Studies, Female, Ischaemic heart disease, Cardiology and Cardiovascular Medicine, business, Research Article
Abstract: Background Left ventricular global longitudinal strain (GLS) with cardiovascular magnetic resonance (CMR) is an important prognostic biomarker. Its everyday clinical use is limited due to methodological and postprocessing diversity among the users and vendors. Standardization of postprocessing approaches may reduce the random operator-dependent variability, allowing for comparability of measurements despite the systematic vendor-related differences. Methods We investigated the random component of variability in GLS measurements by optimization steps which incrementally improved observer reproducibility and agreement. Cine images in two-, three- and four-chamber-views were serially analysed by two independent observers using two different CMR-FT softwares. The disparity of outcomes after each series was systematically assessed after a number of stepwise adjustments which were shown to significantly reduce the inter-observer and intervendor bias, resulting standardized postprocessing approach. The final analysis was performed in 44 subjects (ischaemic heart disease n = 15, non-ischaemic dilated cardiomyopathy, n = 19, healthy controls, n = 10). All measurements were performed blind to the underlying group allocation and previous measurements. Inter- and intra-observer variability were tested using Bland-Altman analyses, intra-class correlation coefficients (ICCs) and coefficients of variation (CVs). Results Compared to controls, mean GLS was significantly lower in patients, as well as between the two subgroups (p Conclusion Standardization of GLS postprocessing helps to reduce the random component of variability, introduced by inconsistencies of and between observers, and also intervendor variability, but not the systematic inter-vendor bias due to differences in image processing algorithms. Standardization of GLS measurements is an essential step in ensuring the reliable quantification of myocardial deformation, and implementation of CMR-FT in clinical routine.
Published: 2019

11. Effect of Alirocumab on Mortality After Acute Coronary Syndromes

Author: Philippe Gabriel, Steg, Michael, Szarek, Deepak L, Bhatt, Vera A, Bittner, Marie-France, Brégeault, Anthony J, Dalby, Rafael, Diaz, Jay M, Edelberg, Shaun G, Goodman, Corinne, Hanotin, Robert A, Harrington, J Wouter, Jukema, Guillaume, Lecorps, Kenneth W, Mahaffey, Angèle, Moryusef, Petr, Ostadal, Alexander, Parkhomenko, Robert, Pordy, Matthew T, Roe, Pierluigi, Tricoci, Robert, Vogel, Harvey D, White, Andreas M, Zeiher, and Gregory G, Schwartz
Subjects: Male, Injections, Subcutaneous, Hypercholesterolemia, alirocumab, Antibodies, Monoclonal, Humanized, Corrections, acute coronary syndrome, Double-Blind Method, Original Research Articles, Humans, PCSK9 protein, Aged, cholesterol, Cholesterol, LDL, Middle Aged, mortality, Treatment Outcome, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Drug Therapy, Combination, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Follow-Up Studies
Abstract: Supplemental Digital Content is available in the text., Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P
Published: 2019

12. Revacept, a Novel Inhibitor of Platelet Adhesion, in Patients Undergoing Elective PCI—Design and Rationale of the Randomized ISAR-PLASTER Trial

Author: Danny Kupka, Sarah Gschwendtner, Heribert Schunkert, Dirk Sibbing, Raphaela Hilz, Marion Janisch, Andreas M. Zeiher, Ralph Hein-Rothweiler, Stefanie Schüpke, Karl-Ludwig Laugwitz, Steffen Massberg, Gjin Ndrepepa, Tommaso Gori, Katharina Mayer, Adnan Kastrati, and Isabell Bernlochner
Subjects: Adult, Blood Platelets, Male, 0301 basic medicine, Platelet Aggregation, medicine.medical_treatment, Myocardial Infarction, Hemorrhage, Coronary Artery Disease, 030204 cardiovascular system & hematology, law.invention, Placebos, Young Adult, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Double-Blind Method, Fibrinolytic Agents, Randomized controlled trial, law, Germany, Antithrombotic, medicine, Clinical endpoint, Humans, Bivalirudin, Aged, Glycoproteins, Aged, 80 and over, Heparin, business.industry, Dual Anti-Platelet Therapy, Percutaneous coronary intervention, Hematology, Hirudins, Middle Aged, Survival Analysis, Peptide Fragments, Recombinant Proteins, Immunoglobulin Fc Fragments, Clinical trial, 030104 developmental biology, Elective Surgical Procedures, Anesthesia, Conventional PCI, Female, Elective Surgical Procedure, business, medicine.drug
Abstract: Despite dual antiplatelet therapy patients undergoing percutaneous coronary intervention (PCI) continue to experience periprocedural ischemic events. In addition, all currently used antithrombotic drugs increase the bleeding risk. Thus, there is an unmet clinical need for antithrombotic strategies with improved efficacy and no increase in bleeding. Revacept is a novel, lesion-directed antithrombotic drug that does not interfere with the function of circulating platelets. This dimeric fusion protein of the extracellular domain of glycoprotein VI (the major platelet collagen receptor) and the human Fc-fragment inhibits collagen-mediated platelet adhesion and subsequent aggregation at the site of vascular injury. The randomized, double-blinded, phase II ISAR-PLASTER trial is based on extensive preclinical evaluation of Revacept and a favorable first-in-man trial. A total of 332 patients with stable coronary artery disease undergoing elective PCI will be randomized to either Revacept 160 mg, Revacept 80 mg, or placebo administered as single intravenous infusion directly before the intervention, on top of standard dual antiplatelet therapy and either heparin or bivalirudin, based on local practice and current guidelines. The primary endpoint is the composite of death or myocardial injury (defined as increase in high sensitivity troponin T ≥ 5 times the upper limit of normal) at 48 hours. The safety endpoint is bleeding of class 2 or higher according to the Bleeding Academic Research Consortium at 30 days. This phase II randomized, double blind trial will assess for the first time the efficacy and safety of Revacept—a lesion-directed inhibitor of platelet adhesion—in patients undergoing elective PCI.
Published: 2019

13. Aortic valve replacement in patients with preexisting liver disease: Transfemoral approach with favorable survival

Author: Silvia Mas-Peiro, Thomas Walther, Jessica Zappel, Andreas M. Zeiher, Philipp C Seppelt, Stephan Fichtlscherer, Mariuca Vasa-Nicotera, Helge Weiler, and Nestoras Papadopoulos
Subjects: Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, 030204 cardiovascular system & hematology, Risk Assessment, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Aortic valve replacement, Valve replacement, Risk Factors, Catheterization, Peripheral, medicine, Risk of mortality, Humans, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Renal replacement therapy, Aged, Retrospective Studies, Aged, 80 and over, Heart Valve Prosthesis Implantation, business.industry, Proportional hazards model, Liver Diseases, Aortic Valve Stenosis, General Medicine, Perioperative, Middle Aged, medicine.disease, Surgery, Femoral Artery, Stenosis, Treatment Outcome, Aortic Valve, Female, Cardiology and Cardiovascular Medicine, business
Abstract: INTRODUCTION The treatment of aortic stenosis has been revolutionized by transcatheter aortic valve replacement (TAVR), but the experience in patients with liver disease is limited. To address this open question, we report the outcome of patients with liver disease undergoing surgical aortic valve replacement (SAVR), transapical (TA), and transfemoral (TF) TAVR. METHODS AND RESULTS Between January 2004 and August 2016, 4,394 patients received aortic valve replacement at our institution. We identified 85 patients (mean follow-up 504 ± 733 days, age 73.4 ± 9.2 years, 44.7% female) with preexisting liver disease (median model of end-stage liver disease score 11, MELD-Na), who underwent TF-TAVR (n = 30), TA-TAVR (n = 13), or SAVR (n = 42). Baseline Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) and of Mortality and Morbidity (STS-PROMM) were the lowest in SAVR patients (related to TF- and TA-TAVR, both p
Published: 2019

14. Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel: a pre-specified exploratory analysis from the TROPICAL-ACS trial

Author: András Komócsi, Csaba András Dézsi, Tobias Geisler, Andreas E. May, Béla Merkely, Róbert Gábor Kiss, Zenon Huczek, Andreas Mügge, Daniel Aradi, Steffen Massberg, Lesca M. Holdt, Imre Ungi, Kurt Huber, Andreas M. Zeiher, Franz-Josef Neumann, Lisa Gross, Martin Hadamitzky, Dietmar Trenk, Lukasz Koltowski, Dirk Sibbing, Konstantinos D. Rizas, and Zoltán Ruzsa
Subjects: Blood Platelets, Male, medicine.medical_specialty, Acute coronary syndrome, Randomization, Prasugrel, Platelet Function Tests, Myocardial Infarction, Hemorrhage, 030204 cardiovascular system & hematology, Risk Assessment, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Ischemia, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Stroke, Aged, business.industry, Hazard ratio, Middle Aged, medicine.disease, Clopidogrel, Death, Treatment Outcome, Case-Control Studies, Cardiology, Drug Therapy, Combination, Female, Cardiology and Cardiovascular Medicine, business, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors, medicine.drug
Abstract: Aims The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. Methods and results Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2–5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57–1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47–1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01–4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18–2.56), P = 0.005], without interaction (P int = 0.76) between study groups. Conclusion Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.
Published: 2019

15. Bone marrow and plasma FGF‐23 in heart failure patients: novel insights into the heart–bone axis

Author: Stephan Fichtlscherer, Stefanie Dimmeler, Florian Seeger, Andreas M. Zeiher, Kateryna Sopova, David M. Leistner, Jörg Honold, Lars Palapies, Till Keller, Birgit Aßmus, and Beatrice von Jeinsen
Subjects: Adult, Male, Fibroblast growth factor 23, medicine.medical_specialty, Fibroblast growth factor, Renal function, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Interquartile range, Original Research Articles, Internal medicine, Humans, Medicine, Original Research Article, 030212 general & internal medicine, Klotho Proteins, Outcome, Glucuronidase, Retrospective Studies, Heart Failure, Ejection fraction, business.industry, Hazard ratio, Middle Aged, Prognosis, medicine.disease, Risk prediction, Confidence interval, Fibroblast Growth Factors, Fibroblast Growth Factor-23, Treatment Outcome, medicine.anatomical_structure, Heart failure, Cardiology, Female, Bone marrow, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients. Methods and results We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P
Published: 2019

16. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial

Author: Michael, Szarek, Harvey D, White, Gregory G, Schwartz, Marco, Alings, Deepak L, Bhatt, Vera A, Bittner, Chern-En, Chiang, Rafael, Diaz, Jay M, Edelberg, Shaun G, Goodman, Corinne, Hanotin, Robert A, Harrington, J Wouter, Jukema, Takeshi, Kimura, Robert Gabor, Kiss, Guillaume, Lecorps, Kenneth W, Mahaffey, Angèle, Moryusef, Robert, Pordy, Matthew T, Roe, Pierluigi, Tricoci, Denis, Xavier, Andreas M, Zeiher, Ph Gabriel, Steg, and Rushton-Smith, Sophie
Subjects: Male, total events, Antibodies, Monoclonal, food and beverages, alirocumab, Middle Aged, Antibodies, Monoclonal, Humanized, acute coronary syndrome, Humans, Drug Therapy, Combination, Female, ddc:610, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Aged, Follow-Up Studies
Abstract: Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18, 924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. Results: With 3, 064 first and 5, 425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
Published: 2019

17. CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping

Author: Faraz Pathan, Gerry Carr-White, Eike Nagel, Hubert Serve, Sarah Lindner, Tommaso D'Angelo, H Zhou, Thomas J. Vogl, Gesine Bug, Andreas M. Zeiher, Silvia Valbuena-López, Hafisyatul Zainal, Valentina O. Puntmann, Christophe A. Arendt, and Jasmin D. Haslbauer
Subjects: Male, Cardiac function curve, medicine.medical_specialty, T2 mapping, Cardiovascular magnetic-resonance, Magnetic Resonance Imaging, Cine, Antineoplastic Agents, 030204 cardiovascular system & hematology, Task-force, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, Anthracycline cardiotoxicity, medicine, Humans, Disease, Society, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Ejection fraction, medicine.diagnostic_test, biology, Heart-failure, business.industry, Myocardium, Cardiovascular magnetic-resonance, Heart-failure, Native T1, Anthracycline cardiotoxicity, Task-force, Therapy, Society, Disease, Echocardiography, Antineoplastic Agents, Biomarkers, Cardiomyopathies, Female, Middle Aged, Reproducibility of Results, Stroke Volume, Cancer, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Troponin, Native T1, Echocardiography, Cine, Heart failure, biology.protein, Cardiology, Therapy, Cardiology and Cardiovascular Medicine, business
Abstract: Cancer-related treatment is associated with development of heart failure and poor outcome in cancer-survivors. T1 and T2 mapping by cardiovascular magnetic resonance (CMR) may detect myocardial injury due to cancer-related treatment.Patients receiving cancer-related treatment regimes underwent screening of cardiac involvement with CMR, either within 3 months (early Tx) or12 months (late Tx) post-treatment. T1 and T2 mapping, cardiac function, strain, ischaemia-testing, scar-imaging and serological cardiac biomarkers were obtained.Compared to age/gender matched controls (n = 57), patients (n = 115, age (yrs): median(IQR) 48(28-60), females, n = 60(52%) had reduced left ventricular ejection fraction (LV-EF) and strain, and higher native T1 and T2. The early Tx group (n = 52) had significantly higher native T1, T2 and troponin levels compared to the late Tx group, indicating myocardial inflammation and oedema (p 0.01). On the contrary, late Tx patients showed raised native T1, increased LV-end-systolic volumes, reduced LV-EF and deformation, and elevated NT-proBNP, suggesting myocardial fibrosis and remodelling (p 0.05). Prospective validation of these results in an independent cohort of patients with similar treatment regimens (n = 25) and longitudinal assessments revealed high concordance of CMR imaging signatures of early and late cardiac involvement.Native T1 and T2 mapping can be valuable in detecting and monitoring of cardiac involvement with cancer-related treatment, providing distinct biosignatures of early inflammatory involvement (raised native T1 and T2) and interstitial fibrosis and remodelling (raised native T1 but not T2), respectively. Our findings may provide an algorithm allowing to identify susceptible myocardium to potentially guide cardio-protective treatment measures.
Published: 2019

18. Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial

Author: Adnan Kastrati, Isabell Bernlochner, Andreas M. Zeiher, Thomas Münzel, David M. Leistner, Alexander Hapfelmeier, Stefanie Schüpke, Gjin Ndrepepa, Heribert Schunkert, Danny Kupka, Karl-Ludwig Laugwitz, Burkert Pieske, Tobias Daniel Trippel, Dirk Sibbing, Oliver Borst, Marion Janisch, Ulf Landmesser, Tommaso Gori, Ralph Hein-Rothweiler, Steffen Massberg, Christian Bradaric, Tobias Petzold, Rainer Okrojek, Meinrad Gawaz, Katharina Mayer, and Stefan Holdenrieder
Subjects: Male, Randomization, Platelet Aggregation, Platelet Function Tests, medicine.medical_treatment, Myocardial Ischemia, Platelet Membrane Glycoproteins, 030204 cardiovascular system & hematology, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Percutaneous Coronary Intervention, Randomized controlled trial, Double-Blind Method, Fibrinolytic Agents, law, Interquartile range, Antithrombotic, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Aged, Glycoproteins, Original Investigation, business.industry, Percutaneous coronary intervention, Middle Aged, Immunoglobulin Fc Fragments, Anesthesia, Female, Cardiology and Cardiovascular Medicine, business, Fibrinolytic agent
Abstract: Importance The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant. Objective To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI. Design, Setting, and Participants A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI). Interventions Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy. Main Outcomes and Measures The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days. Results Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5′-diphosphate–induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36). Conclusions and Relevance Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms. Trial Registration ClinicalTrials.gov Identifier:NCT03312855
Published: 2021

19. Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy

Author: Hakan Akintuerk, Matthias Keuper, Hannah Mellentin, Evelyn Ullrich, Reinhard Dettmeyer, David John, Christian Jux, Anne Schänzer, Andreas M. Zeiher, Luka Nicin, Karin Klingel, A. Sprengel, Dietmar Schranz, Stefan Rupp, Wesley Abplanalp, Stefanie Dimmeler, Jedrzej Hoffmann, and Lukas Tombor
Subjects: Cardiomyopathy, Dilated, Male, 030204 cardiovascular system & hematology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), medicine, Humans, Cardiomyocyte proliferation, Child, 030304 developmental biology, Cause of death, Cell Proliferation, 0303 health sciences, Genetic heterogeneity, business.industry, Sequence Analysis, RNA, High-Throughput Nucleotide Sequencing, Dilated cardiomyopathy, medicine.disease, Large cohort, Cellular heterogeneity, Heart failure, Child, Preschool, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures. Methods: We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types. Results: The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes. Conclusions: Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.
Published: 2021

20. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Author: Kausik K Ray, Helen M Colhoun, Michael Szarek, Marie Baccara-Dinet, Deepak L Bhatt, Vera A Bittner, Andrzej J Budaj, Rafael Diaz, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, J Wouter Jukema, Virginie Loizeau, Renato D Lopes, Angèle Moryusef, Jan Murin, Robert Pordy, Arsen D Ristic, Matthew T Roe, José Tuñón, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, Philippe Gabriel Steg, Gregory G. Schwartz, Ph. Gabriel Steg, Deepak L. Bhatt, Vera A. Bittner, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Harvey D. White, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Guillaume Lecorps, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Patricio López-Jaramillo, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Margus Viigimaa, Markku S. Nieminen, Vakhtang Chumburidze, Nikolaus Marx, Nicolas Danchin, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Zlatko Fras, Anthony J. Dalby, H. Asita de Silva, Emil Hagström, Ulf Landmesser, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez-Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean Van Diepen, Matthew D. Wilson, Andrew T. Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. 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Quintero Ossa, Fernando G Manzur Jatin, Aristides Sotomayor Herazo, Jeffrey Castellanos Parada, Rafael Suarez Arambula, Miguel A Urina Triana, Angela M Fernandez Trujillo, Maja Strozzi, Siniša Car, Melita Jerić, Davor Miličić, Martina Lovrić Benčić, Hrvoje Pintarić, Đeiti Prvulović, Jozica Šikić, Viktor Peršić, Dean Mileta, Kresimir Štambuk, Zdravko Babić, Vjekoslav Tomulic, Josip Lukenda, Stanka Mejic-Krstulovic, Boris Starcevic, Jindrich Spinar, David Horak, Zdenek Velicka, Josef Stasek, David Alan, Vilma Machova, Ales Linhart, Vojtech Novotny, Vladimir Kaucak, Richard Rokyta, Robert Naplava, Zdenek Coufal, Vera Adamkova, Ivo Podpera, Jiri Zizka, Zuzana Motovska, Ivana Marusincova, Premysl Svab, Petr Heinc, Jiri Kuchar, Petr Povolny, Jiri Matuska, Steen H Poulsen, Bent Raungaard, Peter Clemmensen, Lia E Bang, Ole May, Morten Bøttcher, Jens D Hove, Lars Frost, Gunnar Gislason, John Larsen, Peter Betton Johansen, Flemming Hald, Peter Johansen, Jørgen Jeppesen, Tonny Nielsen, Kjeld S 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Detlev Schellenberg, Thomas Heitzer, Ulrich Laufs, Christian Werner, Stephan Gielen, Sebastian Nuding, Bernhard Winkelmann, Steffen Behrens, Karsten Sydow, Mahir Karakas, Gregor Simonis, Thomas Muenzel, Nikos Werner, Stefan Leggewie, Dirk Böcker, Rüdiger Braun-Dullaeus, Nicole Toursarkissian, Michael Jeserich, Matthias Weißbrodt, Tim Schaeufele, Joachim Weil, Heinz Völler, Johannes Waltenberger, Mohammed Natour, Susanne Schmitt, Dirk Müller-Wieland, Stephan Steiner, Lothar Heidenreich, Elmar Offers, Uwe Gremmler, Holger Killat, Werner Rieker, Sotiris Patsilinakos, Athanasios Kartalis, Athanassios Manolis, Dimitrios Sionis, Geargios Chachalis, Ioannis Skoumas, Vasilios Athyros, Panagiotis Vardas, Frangkiskos Parthenakis, Dimitrios Alexopoulos, Georgios Hahalis, John Lekakis, Apostolos Hatzitolios, Sergio R Fausto Ovando, Juan L Arango Benecke, Edgar R Rodriguez De Leon, Bryan PY Yan, David CW Siu, Tibor Turi, Bela Merkely, Imre Ungi, Geza Lupkovics, Lajos Nagy, András Katona, István Édes, Gábor Müller, Iván Horvath, Tibor Kapin, Zsolt Szigeti, József Faluközy, Mukund Kumbla, Manjinder Sandhu, Sharath Annam, Naveen Reddy Proddutur, Reddy Regella, Rajendra K Premchand, Ajaykumar Mahajan, Sudhir Pawar, Atul D Abhyanakar, Prafulla Kerkar, Ravishankar A Govinda, Abraham Oomman, Dhurjati Sinha, Sachin N Patil, Dhiman Kahali, Jitendra Sawhney, Abhijeet B Joshi, Sanjeev Chaudhary, Pankaj Harkut, Santanu Guha, Sanjay Porwal, Srimannarayana Jujjuru, Ramesh B Pothineni, Minguel R Monteiro, Aziz Khan, Shamanna S Iyengar, Jasprakash Singh Grewal, Manoj Chopda, Mahesh C Fulwani, Aparna Patange, Patil Sachin, Vijay K Chopra, Naresh K Goyal, Rituparna Shinde, Gajendra V Manakshe, Nitin Patki, Sumeet Sethi, Vengatesh Munusamy, Sunil Karna, Sunil Thanvi, Srilakshmi Adhyapak, Chandrakant Patil, Ulhas Pandurangi, Rishabh Mathur, Jugal Gupta, Suhas Kalashetti, Ajit Bhagwat, Bagirath Raghuraman, Shiv Kumar Yerra, Prasant Bhansali, Rohidas Borse, Patil Rahul, Srihari Das, Vinay Kumar, Jabir Abdullakutty, Shireesh Saathe, Priya Palimkar, Shireesh Sathe, Shaul Atar, Michael Shechter, Morris Mosseri, Yaron Arbel, Chorin Ehud, Havakuk Ofer, Chaim Lotan, Uri Rosenschein, Amos Katz, Yaakov Henkin, Adi Francis, Marc Klutstein, Eugenia Nikolsky, Robert Zukermann, Yoav Turgeman, Majdi Halabi, Alon Marmor, Ran Kornowski, Michael Jonas, Offer Amir, Yonathan Hasin, Yoseph Rozenman, Shmuel Fuchs, Vered Zvi, Osamah Hussein, Dov Gavish, Zvi Vered, Yoseph Caraco, Mazen Elias, Naveh Tov, Efrat Wolfovitz, Michael Lishner, Nizar Elias, Giancarlo Piovaccari, Annamaria De Pellegrin, Raffaella Garbelotto, Gabriele Guardigli, Valgimigli Marco, Giovanni Licciardello, Carla Auguadro, Filippo Scalise, Claudio Cuccia, Alessandro Salvioni, Giuseppe Musumeci, Michelle Senni, Paolo Calabrò, Salvatore Novo, Pompilio Faggiano, Marco Metra, Nicoletta B De Cesare, Sergio Berti, Claudio Cavallini, Enrico Puccioni, Marcello Galvani, Maurizio Tespili, Piermarco Piatti, Michela Palvarini, Giuseppe De Luca, Roberto Violini, Alessandro De Leo, Zoran Olivari, Pasquale Perrone Filardi, Maurizio Ferratini, Vittorio Racca, Kazuoki Dai, Yuji Shimatani, Haruo Kamiya, Kenji Ando, Yoshihiro Takeda, Yoshihiro Morino, Yoshiki Hata, Kazuo Kimura, Koichi Kishi, Ichiro Michishita, Hiroki Uehara, Toshinori Higashikata, Atsushi Hirayama, Keiji Hirooka, Yasuji Doi, Satoru Sakagami, Shuichi Taguchi, Akihiro Koike, Hiroyuki Fujinaga, Shinji Koba, Ken Kozuma, Tomohiro Kawasaki, Yujiro Ono, Masatoshi Shimizu, Yousuke Katsuda, Atsuyuki Wada, Toshiro Shinke, Junya Ako, Kenshi Fujii, Toshiyuki Takahashi, Tomohiro Sakamoto, Koichi Nakao, Yutaka Furukawa, Hiroshi Sugino, Ritsu Tamura, Toshiaki Mano, Masaaki Uematsu, Noriaki Utsu, Kashima Ito, Takuya Haraguchi, Katsuhiko Sato, Yasunori Ueda, Akira Nishibe, Kazuteru Fujimoto, Motomaru Masutani, Jung Han Yoon, Hack-Lyoung Kim, Hun Sik Park, In-Ho Chae, Moo Hyun Kim, Myung Ho Jeong, Seungwoon Rha, Chongjin Kim, Hyo-Soo Kim, Hae Young Kim, Taekjong Hong, Seung-Jea Tahk, Youngkwon Kim, Arija Busmane, Natalija Pontaga, Aldis Strelnieks, Iveta Mintale, Iveta Sime, Zaneta Petrulioniene, Roma Kavaliauskiene, Ruta Jurgaitiene, Gintare Sakalyte, Rimvydas Slapikas, Sigute Norkiene, Nerijus Misonis, Aleksandras Kibarskis, Raimondas Kubilius, Stojko Bojovski, Nensi Lozance, Aleksandar Kjovkaroski, Snezana Doncovska, Tiong Kiam Ong, Sazzli Kasim, Oteh Maskon, Balachandran Kandasamy, Houng B Liew, Wan Mohd Izani Wan Mohamed, Armando García Castillo, Jorge Carrillo Calvillo, Pedro Fajardo Campos, Juan Carlos Núñez Fragoso, Edmundo Alfredo Bayram Llamas, Marco Antonio Alcocer Gamba, Jaime Carranza Madrigal, Luis Gerardo González Salas, Enrique López Rosas, Belinda González Díaz, Eduardo Salcido Vázquez, Alfredo Nacoud Ackar, Guillermo Antonio Llamas Esperón, Carlos Rodolfo Martínez Sánchez, María Guerrero De Leon, Rodrigo Suarez Otero, Guillermo Fanghänel Salmón, Jesús Antonio Pérez Ríos, José Angel Garza Ruíz, Robert W Breedveld, Margriet 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Palmer, B, Wiseman, A, Puri, S, Mohart, A, Ince, C, Flores, E, Wright, S, Cheng, S, Rosenberg, M, Rogers, W, Kosinski, E, Forgosh, L, Waltman, J, Khan, M, Shoukfeh, M, Dagher, G, Cambier, P, Lieber, I, Kumar, P, East, C, Krichmar, P, Hasan, M, White, L, Knickelbine, T, Haldis, T, Gillespie, E, Amidon, T, Suh, D, Arif, I, Abdallah, M, Akhter, F, Carlson, E, D'Urso, M, El-Ahdab, F, Nelson, W, Moriarty, K, Harris, B, Cohen, S, Carter, L, Doty, D, Sabatino, K, Haddad, T, Malik, A, Rao, S, Mulkay, A, Jovin, I, Klancke, K, Malhotra, V, Devarapalli, S, Koren, M, Chandna, H, Dodds III, G, Goraya, T, Bengston, J, Janik, M, Moran, J, Sumner, A, Kobayashi, J, Davis, W, Yazdani, S, Pasquini, J, Thakkar, M, Vedere, A, Leimbach, W, Rider, J, Fenton, S, Singh, N, Shah, A, Janosik, D, Pepine, C, Berman, B, Gelormini, J, Daniels, C, Richard, K, Keating, F, Kondo, N, Shetty, S, Levite, H, Waider, W, Takata, T, Abu-Fadel, M, Shah, V, Izzo, M, Kumar, A, Hattler, B, Do, R, Link, C, Bortnick, A, Kinzfogl 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Jaffrani, N, Banuru, S, Fisher, D, Xenakis, M, Perlmutter, N, Bhagwat, R, Strader, J, Blonder, R, Akyea-Djamson, A, Labroo, A, Marais, H, Claxton, E, Weiss, R, Kathryn, R, Berk, M, Joshi, P, Khera, A, Khaira, A, Kumkumian, G, Lupovitch, S, Purow, J, Welka, S, Hoffman, D, Fischer, S, Soroka, E, Eagerton, D, Pancholy, S, Ray, M, Erenrich, N, Farrar, M, Pollock, S, French, W, Diamantis, S, Guy, D, Gimple, L, Neustel, M, Schwartz, S, Pereira, E, Albert, S, Spriggs, D, Strain, J, Mittal, S, Vo, A, Chane, M, Hall, J, Vijay, N, Lotun, K, Lester, F, Nahhas, A, Pope, T, Nager, P, Vohra, R, Sharma, M, Bashir, R, Ahmed, H, Berlowitz, M, Fishberg, R, Barrucco, R, Yang, E, Radin, M, Sporn, D, Stapleton, D, Eisenberg, S, Landzberg, J, Mcgough, M, Turk, S, Schwartz, M, Sundram, P, Jain, D, Zainea, M, Bayron, C, Karlsberg, R, Dohad, S, Lui, H, Keen, W, Westerhausen, D, Khurana, S, Agarwal, H, Birchem, J, Penny, W, Chang, M, Murphy, S, Henry, J, Schifferdecker, B, Gilbert, J, Chalavarya, G, Eaton, C, Schmedtje, J, Christenson, S, Dotani, I, Denham, D, Macdonell, A, Gibson, P, Rahman, A, Al Joundi, T, Assi, N, Conrad, G, Kotha, P, Love, M, Giesler, G, Rubenstein, H, Gamil, D, Akright, L, Krawczyk, J, Cobler, J, Wells, T, Welker, J, Foster, R, Gilmore, R, Anderson, J, Jacoby, D, Gardner, G, Dandillaya, R, Vora, K, Kostis, J, Hunter, J, Laxson, D, Ball, E, Egydio, F, Kawakami, A, Oliveira, J, Wozniak, J, Matthews, A, Ratky, C, Valiris, J, Berdan, L, Hepditch, A, Quintero, K, Rorick, T, Westbrook, M, Pascual, A, Rovito, C, Bezault, M, Drouet, E, Simon, T, Alsweiler, C, Luyten, A, Butters, J, Griffith, L, Shaw, M, Grunberg, L, Islam, S, Bregeault, M, Bougon, N, Faustino, D, Fontecave, S, Murphy, J, Verrier, M, Agnetti, V, Andersen, D, Badreddine, E, Bekkouche, M, Bouancheau, C, Brigui, I, Brocklehurst, M, Cianciarulo, J, Devaul, D, Domokos, S, Gache, C, Gobillot, C, Guillou, S, Healy, J, Heath, M, Jaiwal, G, Javierre, C, Labeirie, J, Monier, M, Morales, U, Mrabti, A, Mthombeni, B, Okan, B, Smith, L, Sheller, J, Sopena, S, Pellan, V, Benbernou, F, Bengrait, N, Lamoureux, M, Kralova, K, Scemama, M, Bejuit, R, Coulange, A, Berthou, C, Repincay, J, Lorenzato, C, Etienne, A, Gouet, V, Normand, M, Ourliac, A, Rondel, C, Adamo, A, Beltran, P, Barraud, P, Dubois-Gache, H, Halle, B, Metwally, L, Mourgues, M, Sotty, M, Vincendet, M, Cotruta, R, Chengyue, Z, Fournie-Lloret, D, Morrello, C, Perthuis, A, Picault, P, Zobouyan, I, Dempsey, M, Mcclanahan, M, ODYSSEY OUTCOMES Comm Investigato, and Ege Üniversitesi
Subjects: Male, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, STATIN THERAPY, blood-glucose, Endocrinology, Diabetes and Metabolism, GUIDELINES, PCSK9, 0302 clinical medicine, Endocrinology, GENETIC-VARIANTS, Cardiovascular Disease, Diabetes Complication, Aged Antibodies, Monoclonal, Humanized / therapeutic use* Cardiovascular Diseases / blood Cardiovascular Diseases / prevention & control* Diabetes Complications / blood Diabetes Complications / prevention & control* Female Humans Male Middle Aged Substances, Clinical endpoint, Medicine, guidelines, 030212 general & internal medicine, Prediabetes, Myocardial infarction, myocardial-infarction, genetic-variants, statin therapy, risk, pcsk9, association, liraglutide, evolocumab, RISK, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, BLOOD-GLUCOSE, ASSOCIATION, Middle Aged, Cardiovascular Diseases, Female, Life Sciences & Biomedicine, Human, medicine.medical_specialty, Acute coronary syndrome, PCSK9 inhibitor, acute coronary syndrome, lipoprotein(a), low-density lipoprotein cholesterol, 030209 endocrinology & metabolism, Antibodies, Monoclonal, Humanized, Diabetes Complications, Endocrinology & Metabolism, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, Humans, Aged, Alirocumab, diabetes, PCSK9, hyperlipidemia, Science & Technology, ODYSSEY OUTCOMES Committees and Investigators, business.industry, Unstable angina, EVOLOCUMAB, medicine.disease, MYOCARDIAL-INFARCTION, LIRAGLUTIDE, Human medicine, business
Abstract: Doi, Yasuji/0000-0002-8368-0827; galvani, marcello/0000-0001-5897-667X; Gislason, Gunnar H/0000-0002-0548-402X; Taskinen, Marja-Riitta/0000-0002-6229-3588; Sherwood, Matthew/0000-0002-4305-5883; Malynovsky, Yaroslav V/0000-0002-9118-1104; Viktorova, vic-inna@mail.ru I.A./0000-0001-8728-2722; bastos, jose/0000-0002-9526-3123; Yang, Eric H/0000-0003-4889-7454; Rudenko, Anatoliy Viktorovich/0000-0003-1099-1613; Novotny, Vojtech/0000-0003-3521-9945; Nikolaev, Konstantin/0000-0003-4601-6203; Reshetko, Olga/0000-0003-3107-7636; Leonardi, Sergio/0000-0002-4800-6132; Muenzel, Thomas/0000-0001-5503-4150; Ushakov, Alexei V/0000-0002-7020-4442; Tse, Hung Fat/0000-0002-9578-7808; Podoleanu, Cristian/0000-0001-9987-2519; Raffel, Owen C/0000-0001-5470-7050; Khasanov, Niiaz/0000-0002-7760-0763; Chumakova, Galina A/0000-0002-2810-6531; Ersanli, Murat/0000-0003-1847-3087; cornel, jan hein/0000-0002-1006-2112; Abbate, Antonio/0000-0002-1930-785X; Racca, Vittorio/0000-0002-4465-3789; Urina-Triana, Miguel A/0000-0001-6003-4622; Rasputina, Lesia/0000-0003-1230-4039; Racca, Vittorio/0000-0002-4465-3789; Reis, Gilmar/0000-0002-4847-1034; Sandhu, Manjinder/0000-0003-2538-2079; Keskin, Kudret/0000-0002-9049-1530; PAREPA, IRINEL/0000-0002-7571-9015; Manakshe, Gajendra/0000-0002-4983-4271; Nicolau, Jose C/0000-0002-9680-3689; Strelnieks, Aldis/0000-0003-3493-2562; Budaj, Andrzej/0000-0002-6395-2098; Marin, Francisco/0000-0001-7246-7708; Wongpraparut, Nattawut/0000-0002-1541-3313; Yuan, Zuyi/0000-0002-4141-0298; Jeong, Myung Ho/0000-0003-2424-810X; Mostovoy, Yuriy/0000-0002-7041-1230; Pepine, Carl/0000-0002-6011-681X; Lopez-Jaramillo, Patricio/0000-0002-9122-8742; Garcia-Lledo, Alberto/0000-0002-8986-2584; Tesloianu, Nicolae-Dan/0000-0002-1007-3022; Kosmacheva, Elena/0000-0001-8600-0199; Kunz Sebba Barroso Souza, Weimar/0000-0002-1265-1930; Katz, Amos/0000-0003-0422-934X; Tunon, Jose/0000-0002-1373-0999; Acevedo, Monica/0000-0002-7989-6633; Hove, Jens/0000-0002-5600-5623; Yakushin, Sergey/0000-0001-7202-742X; Gonzalez Juanatey, Jose Ramon/0000-0001-9681-3388; Lyamina, Nadezhda/0000-0001-6939-3234; Aylward, Philip/0000-0002-5358-8552; Apostolovic, Svetlana/0000-0001-9015-297X; Airaksinen, Juhani/0000-0002-0193-568X; Nahhas, Prof. Dr. Ahmed/0000-0002-2887-8187; Barbarash, Olga/0000-0002-4642-3610, WOS: 000475553300016, PubMed: 31272931, Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1: 1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0.65-1.30 mmol/L. in this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA(1c) or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. the primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials. gov, number NCT01663402. Findings At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2.20-2.28 mmol/L), after 4 months' treatment with alirocumab (0.80 mmol/L), or after 4 months' treatment with placebo (2.25-2.28 mmol/L). in the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78-2.46, p, Sanofi; Regeneron Pharmaceuticals, Sanofi and Regeneron Pharmaceuticals.
Published: 2019

21. Myocardial adaptation as assessed by speckle tracking echocardiography after isolated mitral valve surgery for primary mitral regurgitation

Author: Lisa Katharina Wolf, Thomas Puehler, Volker Rudolph, Kavous Hakim-Meibodi, Andreas M. Zeiher, Lech Paluszkiewicz, Hazem Omran, Muhammed Gerçek, Jan Gummert, Henrik Fox, Zisis Dimitriadis, and Lothar Faber
Subjects: Male, medicine.medical_specialty, Time Factors, Databases, Factual, Mitral valve surgery, Speckle tracking echocardiography, Regurgitation (circulation), Strain analysis, 030204 cardiovascular system & hematology, Ventricular Function, Left, Free wall, Myocardial adaptation, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, 030212 general & internal medicine, ddc:610, Cardiac Surgical Procedures, Cardiac imaging, Aged, Original Paper, Mitral regurgitation, Exercise Tolerance, Ventricular Remodeling, business.industry, Mitral Valve Insufficiency, Stroke Volume, Recovery of Function, Middle Aged, Tricuspid Valve Insufficiency, Treatment Outcome, Echocardiography, Concomitant, Ventricular Function, Right, Cardiology, Mitral Valve, Female, Ejection fraction decreased, Cardiology and Cardiovascular Medicine, business
Abstract: The risk of left ventricular (LV) and right ventricular (RV) maladaptation after surgery for isolated primary mitral regurgitation (PMR) is poorly defined. We aimed to evaluate LV and RV contractile function using speckle-tracking analysis alongside with quantification of exercise tolerance in patients with PMR after mitral valve surgery. All consecutive patients with symptomatic PMR undergoing mitral valve surgery between July 2015 and May 2017 were prospectively enrolled. Sequential echocardiographic studies along with clinical assessment were performed before and three months after surgery. Mean age in 138 patients was 65.8 ± 12.7 years, 48.2% (66) of whom were female. Mean LV ejection fraction decreased from 57 ± 12% to 50 ± 11% (p
Published: 2020

22. Association of Clonal Hematopoiesis of Indeterminate Potential With Inflammatory Gene Expression in Patients With Severe Degenerative Aortic Valve Stenosis or Chronic Postischemic Heart Failure

Author: Stefanie Dimmeler, David John, Silvia Mas-Peiro, Andreas M. Zeiher, Sebastian Cremer, and Wesley Abplanalp
Subjects: Male, medicine.medical_treatment, Gene Expression, Disease, 030204 cardiovascular system & hematology, Monocytes, DNA Methyltransferase 3A, 0302 clinical medicine, 030212 general & internal medicine, DNA (Cytosine-5-)-Methyltransferases, Aged, 80 and over, Brief Report, Middle Aged, DNA-Binding Proteins, Cytokine release syndrome, Cytokine, Aortic valve stenosis, Cardiology, Cytokines, Female, Clonal Hematopoiesis, Cardiology and Cardiovascular Medicine, Cytokine Release Syndrome, medicine.medical_specialty, Heterozygote, Antigens, Differentiation, Myelomonocytic, Receptors, Cell Surface, Proinflammatory cytokine, Dioxygenases, 03 medical and health sciences, Antigens, CD, Internal medicine, Proto-Oncogene Proteins, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Humans, Genetic Predisposition to Disease, Aged, Heart Failure, business.industry, Case-control study, COVID-19, Genetic Variation, Aortic Valve Stenosis, medicine.disease, Receptors, Interleukin-6, Heart failure, Case-Control Studies, business, Complication, Transcriptome
Abstract: IMPORTANCE: Cytokine release syndrome is a complication of coronavirus disease 2019. Clinically, advanced age and cardiovascular comorbidities are the most important risk factors. OBJECTIVE: To determine whether clonal hematopoiesis of indeterminate potential (CHIP), an age-associated condition with excess cardiovascular risk defined as the presence of an expanded, mutated somatic blood cell clone in persons without other hematological abnormalities, may be associated with an inflammatory gene expression sensitizing monocytes to aggravated immune responses. DESIGN, SETTING, AND PARTICIPANTS: This hypothesis-generating diagnostic study examined a cohort of patients with severe degenerative aortic valve stenosis or chronic postinfarction heart failure, as well as age-matched healthy control participants. Single-cell RNA sequencing and analyses of circulating peripheral monocytes was done between 2017 and 2019 to assess the transcriptome of circulating monocytes. EXPOSURES: Severe degenerative aortic valve stenosis or chronic postinfarction heart failure. MAIN OUTCOMES AND MEASURES: CHIP-driver sequence variations in monocytes with a proinflammatory signature of genes involved in cytokine release syndrome. RESULTS: The study included 8 patients with severe degenerative aortic valve stenosis, 6 with chronic postinfarction heart failure, and 3 healthy control participants. Their mean age was 75.7 (range, 54-89) years, and 6 were women. Mean CHIP-driver gene variant allele frequency was 4.2% (range, 2.5%-6.9%) for DNMT3A and 14.3% (range, 2.6%-37.4%) for TET2. Participants with DNMT3A or TET2 CHIP-driver sequence variations displayed increased expression of interleukin 1β (no CHIP-driver sequence variations, 1.6217 normalized Unique Molecular Identifiers [nUMI]; DNMT3A, 5.3956 nUMI; P
Published: 2020

23. Value of prognostic nutritional index for survival prediction in trans-catheter aortic valve replacement compared to other common nutritional indexes

Author: Thomas Walther, Philipp C Seppelt, Mariuca Vasa-Nicotera, Andreas M. Zeiher, Roberta De Rosa, Stephan Fichtlscherer, Silvia Mas-Peiro, Jedrzej Hoffmann, and Marie-Isabel Murray
Subjects: Male, medicine.medical_specialty, Multivariate analysis, Catheters, 030204 cardiovascular system & hematology, Gastroenterology, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, 0302 clinical medicine, Aortic valve replacement, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Aged, Retrospective Studies, Aged, 80 and over, biology, Receiver operating characteristic, business.industry, General Medicine, medicine.disease, Prognosis, Catheter, Nutrition Assessment, Cystatin C, Aortic valve stenosis, Aortic Valve, Cohort, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Body mass index
Abstract: Background: Nutritional status predicts outcomes after TAVR. Predictive value of Prognostic Nutritional Index (PNI) was investigated in patients undergoing TAVR, and compared to other nutritional indexes.Methods: A cohort of 114 patients undergoing TAVR in a high-volume centre was studied. A prospective 1-year follow-up was completed. PNI was estimated as follows: (10 × serum albumin[g/dl])+(0.005 × total lymphocytes [1000/μl]). One-year survival was compared in patients with PNI above vs below median; Kaplan-Meier curves were created. A multivariate analysis was used to assess predictive value of PNI for 1-year mortality. ROC curves were used to assess discrimination by PNI, and to compare it with Geriatric Nutritional Risk Index (GNRI) and Body Mass Index (BMI).Results: Mean age was 82.2 years, 59.6% were male. Mean PNI was 46 ± 5. Pre-procedurally, no differences were found between patients with high vs. low PNI. One-year mortality was significantly higher in patients with low PNI values (19/57 vs. 4/57; p < .001). Complications did not differ. A higher PNI predicted 1-year survival, even after adjusting for clinical factors (model 1: HR 0.8, 95% CI 0.7-0.9, p < .0001) and laboratory parameters (NT-proBNP, IL-6, CRP, eGFR, cystatin C, haemoglobin) (model 2: HR 0.8, 95% CI 0.7-0.9, p < .05). ROC curves revealed a stronger predictive value for PNI (AUC 0.80) compared to GNRI (0.77) and BMI (0.6). The optimal cut-off for PNI was 45.Conclusion: PNI is a useful and practical nutritional marker reflecting malnutrition and inflammation prior to the intervention, and strongly predicts 1-year survival. PNI seems to be a better prognostic marker than BMI or GNRI after TAVR.
Published: 2020

24. Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure

Author: Wesley Abplanalp, Lena Dorsheimer, Sebastian Cremer, Birgit Assmus, Jedrzej Hoffmann, Andreas M. Zeiher, Mariuca Vasa-Nicotera, Graziella Becker-Pergola, Stefanie Dimmeler, David John, and Michael A. Rieger
Subjects: 0301 basic medicine, Adult, Male, Physiology, CD14, Cell, Inflammation, 030204 cardiovascular system & hematology, Biology, CD16, Fatty Acid-Binding Proteins, Monocytes, Flow cytometry, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Immune system, Physiology (medical), medicine, Humans, RNA-Seq, Wnt Signaling Pathway, Aged, Heart Failure, medicine.diagnostic_test, Monocyte, Gene Expression Profiling, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Phenotype, Heart failure, Case-Control Studies, Immunology, Female, medicine.symptom, Single-Cell Analysis, Cardiology and Cardiovascular Medicine, Transcriptome
Abstract: Aims Identification of signatures of immune cells at single-cell level may provide novel insights into changes of immune-related disorders. Therefore, we used single-cell RNA-sequencing to determine the impact of heart failure on circulating immune cells. Methods and results We demonstrate a significant change in monocyte to T-cell ratio in patients with heart failure, compared to healthy subjects, which were validated by flow cytometry analysis. Subclustering of monocytes and stratification of the clusters according to relative CD14 and FCGR3A (CD16) expression allowed annotation of classical, intermediate, and non-classical monocytes. Heart failure had a specific impact on the gene expression patterns in these subpopulations. Metabolically active genes such as FABP5 were highly enriched in classical monocytes of heart failure patients, whereas β-catenin expression was significantly higher in intermediate monocytes. The selective regulation of signatures in the monocyte subpopulations was validated by classical and multifactor dimensionality reduction flow cytometry analyses. Conclusion Together this study shows that circulating cells derived from patients with heart failure have altered phenotypes. These data provide a rich source for identification of signatures of immune cells in heart failure compared to healthy subjects. The observed increase in FABP5 and signatures of Wnt signalling may contribute to enhanced monocyte activation.
Published: 2020

25. Analysis of Cell Type-Specific Effects of MicroRNA-92a Provides Novel Insights Into Target Regulation and Mechanism of Action

Author: Chiara Poluzzi, Eva-Maria Rogg, Wesley Abplanalp, Jaya Krishnan, Liliana Schaefer, Marcel H. Schulz, David John, Angelika Bonauer, Corinne Bischof, Andreas M. Zeiher, Stefanie Dimmeler, and Ariane Fischer
Subjects: Male, 0301 basic medicine, Cell signaling, Angiogenesis, Cell type specific, Myocardial Infarction, Oligonucleotides, Biological pathway, Mice, 03 medical and health sciences, Physiology (medical), microRNA, Autophagy, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Myocytes, Cardiac, 3' Untranslated Regions, business.industry, Disease progression, Antagomirs, Rats, Mice, Inbred C57BL, Disease Models, Animal, MicroRNAs, 030104 developmental biology, Mechanism of action, Cancer research, ATP-Binding Cassette Transporters, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Background: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction. Methods: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45 + hematopoietic cells. Results: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3’UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro. Conclusions: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.
Published: 2018

26. Post/preprocedural ratio of hemodynamically assessed aortic regurgitation index as a marker for the need for corrective measures during transcatheter valve replacement: A first confirmatory study in patients receiving a new generation transcatheter self-e

Author: Mariuca Vasa-Nicotera, Silvia Mas-Peiro, Andreas M. Zeiher, Stephan Fichtlscherer, Helge Weiler, and Nestoras Papadopoulos
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Aortic Valve Insufficiency, Hemodynamics, Regurgitation (circulation), 030204 cardiovascular system & hematology, Prosthesis Design, Severity of Illness Index, Prosthesis, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, 0302 clinical medicine, Valve replacement, Predictive Value of Tests, Risk Factors, Internal medicine, Severity of illness, medicine, Humans, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Retrospective Studies, Aged, 80 and over, Observer Variation, medicine.diagnostic_test, business.industry, Reproducibility of Results, Retrospective cohort study, Aortic Valve Stenosis, Recovery of Function, General Medicine, respiratory tract diseases, Treatment Outcome, Aortic Valve, Heart Valve Prosthesis, Predictive value of tests, Angiography, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: OBJECTIVES We aimed to investigate the value of post/preprocedural aortic regurgitation index (ARI) ratio as a marker for more-than-mild aortic regurgitation (AR) after transcatheter aortic valve replacement (TAVR) and as an indication of the need for corrective measures, provided that the implantation depth was acceptable. BACKGROUND Post/preprocedural ARI increases accuracy of residual AR assessment by considering hemodynamic status prior to TAVR. METHODS ARI ratio was calculated in 70 patients undergoing TAVR. ARI ratios were defined as post/preprocedural ARI (ARI ratio 1), and as postcorrective measure/preprocedural ARI (ARI ratio 2). Intraprocedurally, corrective measures use was decided based on angiographically assessed AR severity. The relationship of such decisions to ARI ratios based on a recently proposed threshold (ARI ratio
Published: 2018

27. Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES

Author: Gregory G. Schwartz, Philippe Gabriel Steg, Željko Reiner, Shaun G. Goodman, Pablo Carlos Montenegro Valdovinos, Robert Pordy, Vera Bittner, Harvey D. White, Andreas M. Zeiher, Laurien E Zijlstra, Michael Szarek, J. Wouter Jukema, Hung-Fat Tse, Matthew T. Roe, Rafael Diaz, Deepak L. Bhatt, Heinz Drexel, and Yong-Un Kim
Subjects: Male, medicine.medical_specialty, Acute coronary syndrome, Antibodies, Monoclonal, Humanized / therapeutic use, Treatment outcome, Hypercholesterolemia, 610 Medicine & health, Stroke / drug therapy, Proprotein Convertase 9 / antagonists & inhibitors, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, LDL, acute coronary syndrome, 03 medical and health sciences, 0302 clinical medicine, lipoprotein, LDL, Physiology (medical), Internal medicine, medicine, Humans, cardiovascular diseases, Stroke, Lipoprotein cholesterol, Alirocumab, Aged, business.industry, Hypercholesterolemia / drug therapy, PCSK9 Inhibitors, lipoprotein, Follow up studies, Stroke / blood, cerebrovascular disorders, Middle Aged, medicine.disease, stroke, Hypercholesterolemia / blood, Treatment Outcome, Ischemic stroke, Cardiology, Female, Proprotein Convertase 9 / blood, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background: Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed. Results: Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57−0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57−0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42−1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of 100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity ( P interaction =0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease ( P interaction =0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group. Conclusions: In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.
Published: 2019

28. Native T1 and ECV of Noninfarcted Myocardium and Outcome in Patients With Coronary Artery Disease

Author: Chung-Yao Yu, Andreas Rolf, Tommaso D'Angelo, Rolf Gebker, Faraz Pathan, Sabine Zitzmann, Silvia Valbuena, Rocio Hinojar, Valentina O. Puntmann, Christophe T. Arendt, Eike Nagel, Elen, Jagat Narula, Elif Peker, Andreas M. Zeiher, Sebastian Kelle, Eva Herrmann, Andrew Jabbour, and Gerry Carr-White
Subjects: Adult, Male, medicine.medical_specialty, Acute coronary syndrome, Cardiac Volume, Magnetic Resonance Imaging, Cine, Coronary Artery Disease, 030204 cardiovascular system & hematology, 030218 nuclear medicine & medical imaging, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Cardiac magnetic resonance imaging, Interquartile range, Internal medicine, Clinical endpoint, medicine, Humans, Longitudinal Studies, Prospective Studies, cardiovascular diseases, Stroke, Aged, Aged, 80 and over, Ejection fraction, medicine.diagnostic_test, business.industry, Myocardium, Stroke Volume, coronary artery disease, ischemic heart disease, remodeling, T1 mapping, outcome, Middle Aged, medicine.disease, Treatment Outcome, cardiovascular system, Cardiology, Female, Extracellular Space, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Coronary artery disease (CAD) remains the major cause of cardiac morbidity and mortality worldwide, despite the advances in treatment with coronary revascularization and modern antiremodeling therapy. Risk stratification in CAD patients is primarily based on left ventricular volumes, ejection fraction (LVEF), risk scores, and the presence and extent of late gadolinium enhancement (LGE). The prognostic role of T1 mapping in noninfarcted myocardium in CAD patients has not yet been determined.This study sought to examine prognostic significance of native T1 mapping of noninfarcted myocardium in patients with CAD.A prospective, observational, multicenter longitudinal study of consecutive patients undergoing routine cardiac magnetic resonance imaging with T1 mapping and LGE. The primary endpoint was all-cause mortality. Major adverse cardiocerebrovascular events (MACCE) (cardiac mortality, nonfatal acute coronary syndrome, stroke, and appropriate device discharge) are also reported.A total of 34 deaths and 71 MACCE (n = 665, males n = 424, median age [interquartile range] 57 [22] years; 64%; median follow-up period of 17 [11] months) were observed. Native T1 and extracellular volume were univariate predictors of outcome. Native T1 and LGE were stronger predictors of survival and MACCE compared with extracellular volume, LVEF, cardiac volumes, and clinical scores (p 0.001). Native T1 of noninfarcted myocardium was the sole independent predictor of all-cause mortality (chi-square = 21.7; p 0.001), which was accentuated in the absence of LGE or LVEF ≤35%. For MACCE, native T1 and LGE extent were joint independent predictors (chi-square = 25.6; p 0.001).Characterization of noninfarcted myocardium by native T1 is an important predictor of outcome in CAD patients, over and above the traditional risk stratifiers. The current study's results provide a basis for a novel risk stratification model in CAD based on a complementary assessment of noninfarcted myocardium and post-infarction scar, by native T1 mapping and LGE, respectively.
Published: 2018

29. Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients

Author: Antonella Di Stilo, Massimo Collino, Angela Kornberger, Thomas Braun, Maarten Braspenning, Sandra Atlante, Raffaella Mastrocola, Davide Garella, Massimo Bertinaria, Carsten Kuenne, Harald von Melchner, Fabio Martelli, Frank Schnütgen, Simona Nanni, Germana Zaccagnini, Wim Van Criekinge, Rebecca H. Ritchie, Duran Sürün, Ingrid Fleming, Mattia Mori, Andreas M. Zeiher, Antonella Farsetti, Francesco Spallotta, Valerio Azzimato, Miles J. De Blasio, Manuela Aragno, Chiara Cencioni, Mattia Cocco, Carlo Gaetano, Sven Zukunft, Andres Beiras-Fernandez, Stefan Guenther, and Bruno Botta
Subjects: Male, 0301 basic medicine, Physiology, Population, heart, Biology, Mixed Function Oxygenases, Cytosine, Mice, 03 medical and health sciences, Proto-Oncogene Proteins, fibroblasts, Human Umbilical Vein Endothelial Cells, Animals, Humans, Myocytes, Cardiac, Epigenetics, Enzyme Inhibitors, education, Cells, Cultured, Epigenomics, Demethylation, education.field_of_study, DNA methylation, epigenomics, hyperglycemia, metabolism, physiology, cardiology and cardiovascular medicine, Mesenchymal Stem Cells, Settore MED/13 - ENDOCRINOLOGIA, Base excision repair, Molecular biology, Thymine DNA Glycosylase, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, DNA demethylation, Diabetes Mellitus, Type 2, Ketoglutaric Acids, Thymine-DNA glycosylase, Cardiology and Cardiovascular Medicine, Oxidation-Reduction
Abstract: Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response. Conclusions: Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.
Published: 2018

30. Heparin Induces the Mobilization of Heart-Derived Multipotent Mesoangioblasts During Cardiac Surgery With Cardiopulmonary Bypass or Cardiac Catheterization

Author: Masamichi Koyanagi, Yoshihiro Yamamoto, Stefanie Dimmeler, Yoshihiro Hata, Daisuke Sato, Andreas M. Zeiher, Miyuki Nakano, Chiharu Enoki, Haengnam Park, Yasushi Adachi, Hiroshi Kishimoto, Keisuke Fujitaka, Kensaku Wada, Naoki Minato, Masayoshi Iwasaki, Keita Horitani, and Ichiro Shiojima
Subjects: Male, 0301 basic medicine, Cardiac Catheterization, medicine.medical_specialty, medicine.medical_treatment, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Cardiopulmonary bypass, Humans, Heart Atria, Progenitor cell, Coronary sinus, Aged, Cardiac catheterization, Aged, 80 and over, Cardiopulmonary Bypass, Heparin, Hepatocyte Growth Factor, business.industry, Mesenchymal Stem Cells, General Medicine, Middle Aged, Cardiac surgery, 030104 developmental biology, Cardiology, Female, Hepatocyte growth factor, Cardiology and Cardiovascular Medicine, business, Blood sampling, medicine.drug
Abstract: BACKGROUND We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. CONCLUSIONS Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.
Published: 2018

31. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial

Author: Dirk Sibbing, Dániel Aradi, Claudius Jacobshagen, Lisa Gross, Dietmar Trenk, Tobias Geisler, Martin Orban, Martin Hadamitzky, Béla Merkely, Róbert Gábor Kiss, András Komócsi, Csaba A Dézsi, Lesca Holdt, Stephan B Felix, Radoslaw Parma, Mariusz Klopotowski, Robert H G Schwinger, Johannes Rieber, Kurt Huber, Franz-Josef Neumann, Lukasz Koltowski, Julinda Mehilli, Zenon Huczek, Steffen Massberg, Zofia Parma, Maciej Lesiak, Anna Komosa, Michal Kowara, Bartosz Rymuza, Lukasz Malek, Daniel Aradi, Gábor Veress, András Döme Dézsi, Árpád Lux, Judit Papp, Andrea Kovács, Csaba András Dézsi, Sayour Amer, Zoltán Ruzsa, Szilárd Róna, Renáta Ili, Imre Ungi, Ferenc Nagy, Robert Zweiker, Gábor Tóth-Gayor, Paul Haller, Wolfgang von Scheidt, Andreas Blüthgen, Stefan Leggewie, Hans Ulrich Kreider-Stempfle, Thomas Remp, Kaffer Kara, Andreas Mügge, Alexander Wutzler, Stephan Fichtlscherer, Andreas M. Zeiher, Florian Seeger, Martin Hinterseer, Andreas König, Susanne Lederle, Frauke Czepluch, Lars Maier, Wolfgang Schillinger, Samuel Sossalla, Astrid Hummel, Stephan Felix, Mahir Karakas, Karsten Sydow, Tanja Rudolph, Marcel Halbach, Tommaso Gori, Thomas Münzel, Andreas May, Carsten-Manuel Gerstenberg, David Pilecky, Markus Deichstetter, Stefan Kääb, Anja Löw, Matthias Orban, Stefan Sattler, Sabine Deuschl, Daniel Teupser, Harald Mudra, Thomas Räder, Torsten Schütz, Felix Vahldiek, Dimitar Divchev, Hüseyin Ince, Christoph A Nienaber, Henning Radunski, Peter Boekstegers, Jan Horstkotte, Ralf Mueller, Karin Müller, Robert Schwinger, and Oliver Rasp
Subjects: Male, medicine.medical_specialty, Acute coronary syndrome, Ticlopidine, Prasugrel, Platelet Function Tests, medicine.medical_treatment, Myocardial Infarction, Hemorrhage, 030204 cardiovascular system & hematology, Drug Administration Schedule, law.invention, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Acute Coronary Syndrome, business.industry, Standard treatment, Percutaneous coronary intervention, General Medicine, Middle Aged, Clopidogrel, medicine.disease, 3. Good health, Surgery, Europe, Stroke, Female, Drug Monitoring, business, Prasugrel Hydrochloride, Ticagrelor, Platelet Aggregation Inhibitors, medicine.drug
Abstract: Summary Background Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). Methods In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. Findings Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (p non-inferiority =0·0004; hazard ratio [HR] 0·81 [95% CI 0·62–1·06], p superiority =0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; p non-inferiority =0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59–1·13]; p=0·23). Interpretation Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. Funding Klinikum der Universitat Munchen, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.
Published: 2017

32. Transcoronary Concentration Gradient of microRNA-133a and Outcome in Patients With Coronary Artery Disease

Author: Jes-Niels Boeckel, Stephan Fichtlscherer, Salvatore De Rosa, Stefanie Dimmeler, Till Keller, David M. Leistner, Andreas M. Zeiher, and Roberta De Rosa
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, Revascularization, Disease-Free Survival, Coronary artery disease, 03 medical and health sciences, Coronary circulation, Percutaneous Coronary Intervention, 0302 clinical medicine, Restenosis, Risk Factors, Coronary Circulation, Germany, Internal medicine, Humans, Medicine, cardiovascular diseases, Myocardial infarction, Survival rate, business.industry, Percutaneous coronary intervention, Middle Aged, Prognosis, medicine.disease, Coronary Vessels, Survival Rate, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Mace, Follow-Up Studies
Abstract: Circulating levels of microRNA (miR)-133a are increased in patients with coronary atherosclerotic disease (CAD). Whether the cardiac release of this miR provides any prognostic information in patients with CAD is currently unknown. We aimed to investigate if changes in concentration of miR-133a trough the coronary circulation may be associated with patients' cardiovascular outcome. We enrolled 111 patients (82 with stable CAD and 29 with acute coronary syndromes [ACS]) who underwent coronary angiography. Circulating levels of miR-133a were measured across the transcoronary circulation. Major adverse cardiac events (MACE: death, nonfatal myocardial infarction, and need for revascularization) were recorded through a median follow-up of 32 months. An increased transcoronary concentration gradient of miR133a showed a significant association with overall rate of MACE at follow-up in patients with both stable CAD and ACS (p = 0.011 and p = 0.002, respectively). At the single end point-analysis, increased transcoronary concentration gradients of miR133a were significantly associated with increased rate of death in patients with ACS (p = 0.017) and with increased incidence of new revascularization because of in-stent restenosis in patients with stable CAD (p = 0.026). Kaplan-Meier curves showed a significantly worse event-free survival in patients with greater transcoronary gradients of miR133a (p = 0.026 in stable CAD group and p = 0.007 for ACS group). Nevertheless, these findings lost their significance after adjustment for common cardiovascular risk factor and high-sensitivity troponin-T. In conclusions, the release of miR133a, as measured by its transcoronary concentration gradient, is associated with a higher incidence of MACE in patients with CAD, but it does not add significant prognostic information compared with traditional prognostic biomarkers, therefore limiting its potential usefulness in the clinical practice. Nevertheless, the differential modulation of miR-133a release in the coronary circulation may reflect pathophysiological mechanism involved in CAD progression and complications and suggest a novel potential role for this miR in the development of in-stent restenosis.
Published: 2017

33. Coronary Atherosclerotic Plaque Characteristics and Cardiovascular Risk Factors ― Insights From an Optical Coherence Tomography Study ―

Author: Jes-Niels Boeckel, Claudia E. Thome, Andreas M. Zeiher, Stephan Fichtlscherer, Roberta De Rosa, Sophia M. Reis, Mariuca Vasa-Nicotera, and David M. Leistner
Subjects: Male, medicine.medical_specialty, Cardiovascular risk factors, Coronary Artery Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, Diabetes Complications, Prediabetic State, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, medicine, Humans, Obesity, Registries, 030212 general & internal medicine, Prediabetes, Coronary atherosclerosis, Aged, Glycemic, business.industry, General Medicine, Middle Aged, medicine.disease, Vulnerable plaque, Plaque, Atherosclerotic, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Tomography, Optical Coherence
Abstract: BACKGROUND The association between cardiovascular risk factors (CVRF) and the risk of coronary events is widely acknowledged. Whether individual risk factors may be associated with distinct plaque characteristics is currently unclear. We investigated the relationship between CVRF and coronary plaque burden and phenotype.Methods and Results:We assessed coronary atherosclerotic plaque characteristics by optical coherence tomography in 67 patients with stable coronary artery disease undergoing coronary angiography. The plaque burden and the distinct plaque phenotypes were compared with regard to different CVRF. Overall plaque burden was significantly greater in patients with diabetes mellitus (P=0.010), prediabetes (P=0.035) and obesity (P=0.024), and correlated with the number of CVRF (R=0.358, P=0.003). Patients with diabetes had a greater extent of fibroatheroma (P=0.015), calcific fibroatheroma (P=0.031), thin-cap fibroatheroma (TCFA-P=0.011) and plaque erosion (P=0.002). Obese patients showed a greater extent of fibroatheroma (P=0.007), TCFA (P=0.015) and macrophage load (P=0.043). The number of CVRF correlated with fibroatheroma (R=0.425, P
Published: 2017

34. Short‐term decrease of left atrial size predicts clinical outcome in patients with severe aortic stenosis undergoing TAVR

Author: Marie-Isabel Murray, Stephan Fichtlscherer, Mariuca Vasa-Nicotera, Andreas M. Zeiher, Dietmar Schranz, Silvia Mas-Peiro, Anoosh Esmaeili, and Roberta De Rosa
Subjects: Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Left atrium, 030204 cardiovascular system & hematology, Patient Readmission, Risk Assessment, Severity of Illness Index, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, 0302 clinical medicine, Valve replacement, Risk Factors, Left atrial, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, In patient, Heart Atria, Prospective Studies, Registries, 030212 general & internal medicine, Lead (electronics), Aged, Aged, 80 and over, Heart Failure, Proportional hazards model, business.industry, Aortic Valve Stenosis, Atrial Remodeling, General Medicine, medicine.disease, Progression-Free Survival, Stenosis, Functional Status, medicine.anatomical_structure, Heart Valve Prosthesis, Heart failure, Cardiology, Atrial Function, Left, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Objectives We investigated whether transcatheter aortic valve replacement (TAVR) results in a short-term decrease in left atrium (LA) size and whether such decrease may predict patients' clinical outcome. Background Increased LA size is a hallmark of severe aortic stenosis (AS) and is associated with adverse patients' cardiovascular outcome. Whether TAVR may lead to a decrease in LA size is not known. Methods and results Hundred and four patients with severe symptomatic AS and dilated LA undergoing TAVR were enrolled. LA volume was assessed by echocardiography before and shortly after TAVR (median time: 7 days). Composite rate of death and hospitalization for acutely decompensated heart failure (HF) was recorded and clinical status was assessed through NYHA-class evaluation at 12 months median follow-up. After TAVR, 49 patients (47%) demonstrated a decrease in LA volume. Despite a similar baseline NYHA class, patients with decrease in LA size had significant better improvement in clinical status respect to patients with unvaried LA size (NYHA post: 1.2 ± 0.6 vs. 1.8 ± 1.1, p = .001; NYHA reduction: -1.6 ± 0.9 vs. -0.9 ± 1.0, p = .002, respectively). Moreover, these patients had a significantly reduced rate of death or HF-hospitalization (4 vs. 29%, p = .001) and a significantly longer event-free-survival from Kaplan-Meier curves (p = .003). COX regression analysis showed that, among echocardiographic parameters, decrease in LA size was an independent predictor of clinical outcome (HR: 0.149, CI: 0.034-0.654, p = .012). Conclusions The lack of decrease in LA size shortly after TAVR is associated with significantly higher rates of death and HF-hospitalization, as well as with impaired improvement in clinical status during long-term follow-up.
Published: 2019

35. A Direct Comparison of Self-Expandable Portico Versus Balloon-Expandable Sapien 3 Devices for Transcatheter Aortic Valve Replacement: A Case-Matched Cohort Study

Author: Silvia, Mas-Peiro, Philipp Christian, Seppelt, Helge, Weiler, Gina-Lisa, Mohr, Nestoras, Papadopoulos, Thomas, Walther, Andreas M, Zeiher, Stephan, Fichtlscherer, and Mariuca, Vasa-Nicotera
Subjects: Aged, 80 and over, Male, Time Factors, Incidence, Hemodynamics, Aortic Valve Stenosis, Prosthesis Design, United States, Survival Rate, Transcatheter Aortic Valve Replacement, Postoperative Complications, Treatment Outcome, Echocardiography, Aortic Valve, Heart Valve Prosthesis, Humans, Female, Prospective Studies, Follow-Up Studies
Abstract: Pairwise comparisons of clinical and hemodynamic outcomes with new transcatheter aortic valve replacement (TAVR) prostheses are needed to help interventionists select the most appropriate device. The self-expandable Portico valve (Abbott Vascular) was compared with the balloon-expandable Sapien 3 valve (Edwards Lifesciences) at a high-volume center in a real-world setting.All patients undergoing TAVR with a new-generation device from March 2015 to September 2017 at a single center were included. Baseline, peri-interventional, and prospective 30-day follow-up data were obtained. A nearest-neighbor propensity-score matching procedure (2:1) was used, based on age, STS score, EuroScore II, New York Heart Association (NYHA) status, and sex. Primary endpoint was 30-day all-cause mortality. Secondary endpoints included procedural results, complications according to Valve Academic Research Consortium (VARC)-2 criteria, and echocardiographic findings.A total of 177 out of 273 patients were matched (104 Portico valves and 73 Sapien 3 valves). Procedural success rates were 99.0% vs 98.6%, respectively; P=NS). Contrast dye use (160 mL for Portico vs 120 mL for Sapien 3; P.001) and fluoroscopy time (19.0 min for Portico vs 15.5 min for Sapien 3; P=.048) were significantly lower with the Sapien 3 device. Thirty-day mortality rate was 5.8% for the Portico group vs 4.1% for the Sapien 3 group (P=.74). Complication rates were similar between Portico and Sapien 3 groups: stroke (2.9% vs 4.1%, respectively; P=.31), major bleeding (3.8% vs 5.5%, respectively; P=.51), major vascular complications (5.8% vs 5.5%, respectively; P=.99), and pacemaker implantation (21.9% vs 17.5%, respectively; P=.55). A more-than-mild paravalvular leak was observed in 8.2% vs 4.5%, respectively (P=NS).Short-term clinical and hemodynamic outcomes were similar with Portico and Sapien 3 prostheses; no statistically significant differences were observed in mortality and major complication rates. An individually tailored prosthesis choice is suggested.
Published: 2019

36. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

Author: Matteo Savoia, Fabio Martelli, Andreas M. Zeiher, Germana Zaccagnini, Lucia Di Marcotullio, Alfredo Pontecorvi, Carlo Gaetano, Sandra Atlante, Chiara Cencioni, Paolo Devanna, Bruno Botta, Mattia Mori, Antonella Farsetti, and Francesco Spallotta
Subjects: Male, Transcriptional Activation, 0301 basic medicine, Transcription, Genetic, Muscle Fibers, Skeletal, Mitochondrion, MyoD, Biochemistry, IDH2, Cell Line, Myoblasts, Mice, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Cell Line, Tumor, Gene expression, PCAF, Genetics, Animals, Humans, Myocyte, mitochondrion, Molecular Biology, metabolism, α-ketoglutarate, Metabolism, Chemistry, Lysine, Acetylation, Cell Differentiation, ?-ketoglutarate, Isocitrate Dehydrogenase, Mitochondria, Cell biology, Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, E1A-Associated p300 Protein, Protein Processing, Post-Translational, C2C12, 030217 neurology & neurosurgery, HeLa Cells, Biotechnology
Abstract: The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N-terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.
Published: 2019

37. Identification of acute myocardial infarction in elderly patients using optimized highly sensitive troponin I thresholds

Author: Thomas Münzel, Karl J. Lackner, Philipp S. Wild, Stergios Tzikas, Tanja Zeller, Till Keller, Christoph Bickel, Fachrie Sar, Marco Tubaro, Beatrice von Jeinsen, Stephan Baldus, Tommaso Gori, Christian W. Hamm, Andreas M. Zeiher, Alexander F. Schmidt, Christoph Liebetrau, Lars Palapies, and Stefan Blankenberg
Subjects: Adult, Male, medicine.medical_specialty, Cardiac troponin, Health, Toxicology and Mutagenesis, health care facilities, manpower, and services, Clinical Biochemistry, Myocardial Infarction, Hyperlipidemias, 030204 cardiovascular system & hematology, Biochemistry, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Troponin I, medicine, Humans, Myocardial infarction, Prospective Studies, cardiovascular diseases, health care economics and organizations, Aged, Aged, 80 and over, biology, business.industry, Smoking, Middle Aged, medicine.disease, Troponin, humanities, Highly sensitive, 030220 oncology & carcinogenesis, Hypertension, Cardiology, biology.protein, Female, business, Biomarkers
Abstract: Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs. Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission. Results: Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis (p Conclusions: hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.
Published: 2019
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38. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Author: M. Ludovica Carerj, Anastasia Shchendrygina, Eike Nagel, Mariuca Vasa-Nicotera, Imke Wieters, Felicitas Escher, Andreas M. Zeiher, Valentina O. Puntmann, Jedrzej Hoffmann, Masia Fahim, Maria J G T Vehreschild, Christophe T. Arendt, and Publica
Subjects: Male, Contrast Media, Gadolinium, 030204 cardiovascular system & hematology, Ventricular Function, Left, Cohort Studies, 0302 clinical medicine, Germany, Medicine, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Original Investigation, Ejection fraction, Troponin T, Stroke volume, Middle Aged, Magnetic Resonance Imaging, Myocarditis, Cardiovascular Diseases, Cohort, Female, Autopsy, Coronavirus Infections, Cardiomyopathies, Cardiology and Cardiovascular Medicine, Cohort study, Adult, medicine.medical_specialty, Pneumonia, Viral, Betacoronavirus, 03 medical and health sciences, Internal medicine, Online First, Humans, ddc:610, Pandemics, Heart Failure, SARS-CoV-2, business.industry, Research, Myocardium, Case-control study, COVID-19, Stroke Volume, Recovery of Function, medicine.disease, Coronavirus, Case-Control Studies, business
Abstract: Key Points Question What are the cardiovascular effects in unselected patients with recent coronavirus disease 2019 (COVID-19)? Findings In this cohort study including 100 patients recently recovered from COVID-19 identified from a COVID-19 test center, cardiac magnetic resonance imaging revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), which was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis. Meaning These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19., This cohort study evaluates the presence of myocardial injury in unselected patients recently recovered from coronavirus disease 2019 (COVID-19)., Importance Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown. Objective To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness. Design, Setting, and Participants In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020. Exposure Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription–polymerase chain reaction on swab test of the upper respiratory tract. Main Outcomes and Measures Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor–matched patients (n = 57). Results Of the 100 included patients, 53 (53%) were male, and the median (interquartile range [IQR]) age was 49 (45-53) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (3 pg/mL or greater) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (13.9 pg/mL or greater) in 5 patients (5%). Compared with healthy controls and risk factor–matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, higher left ventricle mass, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), and pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1122 [1113-1132] ms vs 1143 [1131-1156] ms; P = .02) but not for native T2 mapping or hsTnT levels. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.35; P
Published: 2020

39. Cardiac Troponins for the Diagnosis of Acute Myocardial Infarction in Chronic Kidney Disease

Author: Christoph Bickel, Christoph Wanner, Christiane Drechsler, Thomas Münzel, Georg Fette, Stephan Baldus, Stefan Blankenberg, Beatrice von Jeinsen, Karl J. Lackner, Till Keller, Johannes T Neumann, Tanja Zeller, Daniel Kraus, Lars Palapies, Andreas M. Zeiher, and Stergios Tzikas
Subjects: Male, medicine.medical_specialty, Cardiac troponin, Nephrology and Kidney, Myocardial Infarction, Diagnostic Testing, macromolecular substances, 030204 cardiovascular system & hematology, non‐ST‐segment elevation acute coronary syndrome, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Troponin T, Internal medicine, cohort study, medicine, Humans, Prospective Studies, cardiovascular diseases, ddc:610, 030212 general & internal medicine, Myocardial infarction, Renal Insufficiency, Chronic, Original Research, Aged, Kidney in Cardiovascular Disease, business.industry, Troponin I, Middle Aged, Prognosis, medicine.disease, female genital diseases and pregnancy complications, decision aids, Cardiology, biomarker, Biomarker (medicine), Female, Cardiology and Cardiovascular Medicine, business, Acute Coronary Syndromes, chronic kidney disease, Biomarkers, Follow-Up Studies, Glomerular Filtration Rate, Kidney disease, Cohort study
Abstract: Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST ‐segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE ‐ AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE ‐ AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high‐sensitivity troponin I (hs‐ cTnI ) measurements and 7059 cases from a clinical registry with high‐sensitivity troponin T (hs‐ cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate 2 ). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE ‐ AMI than non‐ CKD patients. The specificities of hs‐ cTnI and hs‐ cTnT to detect NSTE ‐ AMI were reduced with CKD (0.82 versus 0.91 for hs‐ cTnI and 0.26 versus 0.73 for hs‐ cTnT ) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs‐ cTnI ) and 55% (hs‐ cTnT ) of CKD patients. Conclusions The diagnostic performance of high‐sensitivity cardiac troponins in patients with CKD with suspected NSTE ‐ AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.
Published: 2018

40. Identification and regulation of the long non-coding RNA Heat2 in heart failure

Author: Karoline E. Kokot, Stefanie Dimmeler, Wei Chen, Jan Haas, Timon Seeger, Hugo A. Katus, Jes-Niels Boeckel, Benjamin Meder, David John, Niels Grabe, Elham Kayvanpour, Andreas M. Zeiher, Stephan von Haehling, Simone F. Glaser, Andreas W. Heumüller, Nicole Ebner, Florian Leuschner, Till Keller, Maximilian K. Lackner, Maya F. Perret, Stephan Fichtlscherer, Sabine Hünecke, and Christoph Dieterich
Subjects: 0301 basic medicine, Adult, Male, Cell, 030204 cardiovascular system & hematology, Basophil, Peripheral blood mononuclear cell, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, RNA, Messenger, Molecular Biology, Whole blood, Aged, Heart Failure, business.industry, Eosinophil, Middle Aged, medicine.disease, Long non-coding RNA, Eosinophils, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Heart failure, Case-Control Studies, Immunology, Leukocytes, Mononuclear, Female, RNA, Long Noncoding, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Circulating immune cells have a significant impact on progression and outcome of heart failure. Long non-coding RNAs (lncRNAs) comprise novel epigenetic regulators which control cardiovascular diseases and inflammatory disorders. We aimed to identify lncRNAs regulated in circulating immune cells of the blood of heart failure patients. Methods and results Next-generation sequencing revealed 110 potentially non-coding RNA transcripts differentially expressed in peripheral blood mononuclear cells of heart failure patients with reduced ejection fraction. The up-regulated lncRNA Heat2 was further functionally characterized. Heat2 expression was detected in whole blood, PBMNCs, eosinophil and basophil granulocytes. Heat2 regulates cell division, invasion, transmigration and immune cell adhesion on endothelial cells. Conclusion Heat2 is an immune cell enriched lncRNA that is elevated in the blood of heart failure patients and controls cellular functions.
Published: 2018

41. Switch in Laminin beta 2 to Laminin beta 1 Isoforms During Aging Controls Endothelial Cell Functions-Brief Report

Author: Eva-Maria Rogg, Stefan Günther, Emmanouil Chavakis, Julian U. G. Wagner, Stefanie Dimmeler, Andreas M. Zeiher, Simone F. Glaser, Francesca Bonini, Liliana Schaefer, Reinier A. Boon, Marion Muhly-Reinholz, David John, Melanie-Jane Hannocks, Physiology, ACS - Atherosclerosis & ischemic syndromes, and ACS - Microcirculation
Subjects: Male, 0301 basic medicine, Gene isoform, Aging, Integrin, Myocardial Infarction, Neovascularization, Physiologic, Cell Separation, 030204 cardiovascular system & hematology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Laminin, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Animals, Humans, Cells, Cultured, Tissue homeostasis, Cell Proliferation, biology, Chemistry, Integrin beta1, Age Factors, Endothelial Cells, Extracellular Matrix, Cell biology, Mice, Inbred C57BL, Endothelial stem cell, Disease Models, Animal, Phenotype, 030104 developmental biology, Cellular Microenvironment, Gene Expression Regulation, biology.protein, Cardiology and Cardiovascular Medicine, Function (biology), Signal Transduction
Abstract: Objective— Endothelial cells play important roles in tissue homeostasis and vascularization, a function that is impaired by aging. Here, we aim to decipher the role of the microenvironment underlying the impairment of endothelial cell functions by aging. Approach and Results— RNA sequencing of isolated cardiac endothelial cells derived from young and 18-month-old mouse hearts revealed that aging affects the endothelial expression of genes encoding extracellular matrix proteins, specifically the laminin β1 ( Lamb1 ) and laminin β2 ( Lamb2 ) chains. Whereas Lamb1 was upregulated, Lamb2 was decreased in endothelial cells in old mice compared with young controls. A similar change in expression patterns was observed after induction of acute myocardial infarction. Mimicking aging and injury conditions by plating endothelial cells on laminin β1–containing laminin 411 matrix impaired endothelial cell adhesion, migration, and tube formation and augmented endothelial-to-mesenchymal transition and endothelial detachment compared with laminin 421, which contains the laminin β2 chain. Because laminins can signal via integrin receptors, we determined the activation of ITGB1 (integrin β1). Laminin 421 coating induced a higher activation of ITGB1 compared with laminin 411. siRNA-mediated silencing of ITGB1 reduced laminin β2–dependent adhesion, suggesting that laminin β2 more efficiently activates ITGB1. Conclusions— Mimicking age-related modulation of laminin β1 versus β2 chain expression changes the functional properties and phenotype of endothelial cells. The dysregulation of the extracellular matrix during vascular aging may contribute to age-associated impairment of organ function and fibrosis.
Published: 2018

42. High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus

Author: Axel Braner, Karin Klingel, L. Winau, David D'Cruz, Valentina O. Puntmann, Andreas M. Zeiher, Ulrich Drott, Christophe T. Arendt, Gerry Carr-White, Michael S. Marber, Eike Nagel, Katrin Schnoes, Harald Burkhardt, Shirish Sangle, Thomas J. Vogl, Rocio Hinojar Baydes, and Publica
Subjects: Adult, Male, medicine.medical_specialty, Biopsy, Immunology, Inflammation, 030204 cardiovascular system & hematology, General Biochemistry, Genetics and Molecular Biology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Troponin T, Internal medicine, medicine, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, Subclinical infection, medicine.diagnostic_test, biology, business.industry, C-reactive protein, Magnetic resonance imaging, Heart, Middle Aged, Troponin, Magnetic Resonance Imaging, Myocarditis, High sensitivity troponin, Case-Control Studies, biology.protein, Cardiology, Biomarker (medicine), Female, medicine.symptom, business, Biomarkers, Endocardium
Abstract: BackgroundCardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR).Methods and resultsThis is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p2 0.462, pConclusionsPatients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement.Trial registration numerNCT02407197; Results.
Published: 2018

43. Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain

Author: Lars Pieper, Jens Klotsche, Stefan Blankenberg, Stephan Baldus, David M. Leistner, Till Keller, Hans-Ulrich Wittchen, Christoph Bickel, Stergios Tzikas, Soeren L. Kleinhaus, Hendrik Lehnert, Sigmund Silber, Stefanie Dimmeler, Jes-Niels Boeckel, Tanja Zeller, Andreas M. Zeiher, Bertil Lindahl, Lars Palapies, Thomas Münzel, Günter K. Stalla, Maya F. Perret, Winfried Maerz, Beatrice von Jeinsen, and Martinson, Elizabeth
Subjects: Male, Diagnostic Techniques, Cardiovascular, Myocardial Infarction, lcsh:Medicine, 030204 cardiovascular system & hematology, Chest pain, Kidney Function Tests, Cohort Studies, 0302 clinical medicine, Troponin I, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Myocardial infarction, lcsh:Science, education.field_of_study, Multidisciplinary, Kardiologi, Age Factors, Middle Aged, musculoskeletal system, Cardiology, cardiovascular system, Female, medicine.symptom, Glomerular Filtration Rate, Adult, Acute coronary syndrome, medicine.medical_specialty, Chest Pain, Population, Renal function, macromolecular substances, Sensitivity and Specificity, Article, 03 medical and health sciences, Sex Factors, Predictive Value of Tests, Internal medicine, medicine, Humans, ddc:610, cardiovascular diseases, education, Aged, Receiver operating characteristic, business.industry, lcsh:R, medicine.disease, Heart failure, lcsh:Q, business, Biomarkers
Abstract: The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Published: 2018

44. Testosterone is not associated with traits of optimism or pessimism: Observational evidence from the prospective DETECT study

Author: Jens Klotsche, Andreas M. Zeiher, Uwe Koch-Gromus, Robin Haring, Jürgen Hoyer, Lars Pieper, Sigmund Silber, Winfried März, David Pittrow, Hanna Kische, Günter K. Stalla, Hans-Ulrich Wittchen, John Venz, Hendrik Lehnert, and Jonason, Peter Karl
Subjects: Male, Emotions, Prospective data, Social Sciences, Blood Pressure, Biochemistry, Vascular Medicine, Observational evidence, 0302 clinical medicine, Cognition, Medicine and Health Sciences, Medicine, Psychology, Testosterone, Longitudinal Studies, Prospective Studies, Lipid Hormones, media_common, Multidisciplinary, Alcohol Consumption, Depression, Regression analysis, Middle Aged, Experimental research, Pessimism, Research Design, Androgens, Observational Studies, Female, Clinical psychology, Research Article, media_common.quotation_subject, Science, Decision Making, Research and Analysis Methods, 03 medical and health sciences, Optimism, Mental Health and Psychiatry, Humans, ddc:610, Nutrition, business.industry, Mood Disorders, Cognitive Psychology, Biology and Life Sciences, Testosterone (patch), Hormones, 030227 psychiatry, Diet, Cross-Sectional Studies, Cognitive Science, Observational study, business, 030217 neurology & neurosurgery, Neuroscience
Abstract: Background: Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and dispositional optimism / pessimism. Methods: We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models. Results: Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (β-coefficient per unit change in T for men: -0.01 (95% CI: -0.24–0.22), women: 0.08 (-0.03–0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up. Conclusions: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.
Published: 2018

45. Thirty-Day Outcomes in 100 Consecutive Patients Undergoing Transfemoral Aortic Valve Replacement With the Portico Valve on an All-Comer Basis

Author: Silvia, Mas-Peiro, Mariuca, Vasa-Nicotera, Helge, Weiler, Nestoras, Papadopoulos, Roberta, De Rosa, Andreas M, Zeiher, and Stephan, Fichtlscherer
Subjects: Aged, 80 and over, Male, Aortic Valve Stenosis, Prosthesis Design, Survival Analysis, Femoral Artery, Transcatheter Aortic Valve Replacement, Postoperative Complications, Echocardiography, Aortic Valve, Germany, Heart Valve Prosthesis, Catheterization, Peripheral, Outcome Assessment, Health Care, Humans, Female, Aged
Abstract: Transcatheter heart valves such as the self-expandable Portico valve (St. Jude Medical) are being developed to overcome limitations of first-generation devices. Since clinical experience with this valve is still limited in a real-world setting, we investigated its use on an all-comer basis.Between October 2015 and October 2016, a total of 100 consecutive patients assessed for transcatheter aortic valve replacement (TAVR) and found suitable for the Portico valve were included. The primary endpoint was 30-day all-cause mortality. Secondary endpoints included immediate postprocedural survival, complications according to Valve Academic Research Consortium (VARC)-2 criteria, and echocardiographic findings.All 100 participants received a Portico valve; the patient group included 56 women (56%) and 44 men (44%) with mean age of 81.7 ± 5.1 years. Mean EuroScore II and STS scores were 6.2 ± 8.6 and 5.2 ± 6.1, respectively. Immediate postprocedural survival rate was 99%. The 30-day mortality rate (6%) was comparable with earlier studies performed in selected patients. Complications included major stroke (2%), minor stroke (2%), major vascular complication (2%), minor vascular complication (4%), cardiac tamponade (1%), major bleeding (3%), conversion into open surgery (1%), and pacemaker implantation (19.5%). Maximal and mean echocardiographic gradients were reduced from 66 mm Hg (range, 21-141 mm Hg) to 15 mm Hg (range, 4-41 mm Hg) (P.001) and from 44 mm Hg (range, 12-84 mm Hg) to 8 mm Hg (range, 2-25 mm Hg) (P.001), respectively. A low rate of more-than-mild paravalvular leak was observed (4.4%).Our immediate and 30-day post-TAVR results support favorable survival comparable to other studies, and significant clinical improvement with the Portico valve in non-selected patients in a real-world setting, with short-term complications being uncommon.
Published: 2017

46. Improved outcome with repeated intracoronary injection of bone marrow-derived cells within a registry: rationale for the randomized outcome trial REPEAT

Author: Salvatore De Rosa, Eva Hermann, Halvard Bonig, Stefanie Dimmeler, Samer Alakmeh, Wayne C. Levy, Andreas M. Zeiher, and Birgit Assmus
Subjects: Male, Cardiac function curve, medicine.medical_specialty, Myocardial Infarction, Infarction, Bone Marrow Cells, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Risk Factors, law, Internal medicine, medicine, Humans, Prospective Studies, Registries, 030212 general & internal medicine, Myocardial infarction, Prospective cohort study, Aged, Bone Marrow Transplantation, Heart Failure, Ischemic cardiomyopathy, business.industry, Middle Aged, medicine.disease, Surgery, Treatment Outcome, medicine.anatomical_structure, Heart failure, Cardiology, Female, Bone marrow, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post-infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. Methods and results The results of an ongoing single-centre registry including 297 post-infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). Conclusion Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure.
Published: 2015

47. Estimation of Values below the Limit of Detection of a Contemporary Sensitive Troponin I Assay Improves Diagnosis of Acute Myocardial Infarction

Author: Stergios Tzikas, Christoph Bickel, Stefan Blankenberg, Sophia M. Reis, Karl J. Lackner, Lars Palapies, Beatrice von Jeinsen, Jes-Niels Boeckel, Stephan Baldus, Thomas Münzel, Andreas M. Zeiher, Tanja Zeller, and Till Keller
Subjects: Male, medicine.medical_specialty, Clinical Biochemistry, Myocardial Infarction, macromolecular substances, Cohort Studies, Limit of Detection, Internal medicine, Troponin I, medicine, Humans, cardiovascular diseases, Myocardial infarction, Aged, Aged, 80 and over, Detection limit, biology, business.industry, Biochemistry (medical), Area under the curve, Middle Aged, Prognosis, medicine.disease, Troponin, Censoring (statistics), Surgery, ROC Curve, Area Under Curve, Acute Disease, Cohort, cardiovascular system, Cardiology, biology.protein, Regression Analysis, Female, Myocardial infarction diagnosis, business
Abstract: BACKGROUND The limit of detection (LoD) is the minimal amount of a substance that can be consistently detected. In the diagnosis of acute myocardial infarction (AMI) many patients present with troponin concentrations below the LoD of contemporary sensitive cardiac troponin I (cs-cTnI) assays. These censored values below the LoD influence the diagnostic performance of these assays compared to highly sensitive cTnI (hs-cTnI) assays. Therefore we assessed the impact of a new approach for interpolation of the left-censored data of a cs-cTnI assay in the evaluation of patients with suspected AMI. METHODS Our posthoc analysis used a real world cohort of 1818 patients with suspected MI. Data on cs-cTnI was available in 1786 patients. As a comparator the hs-cTnI version of the assay was used. To reconstruct quantities below the LoD of the cs-cTnI assay, a gamma regression approach incorporating the GRACE (Global Registry of Acute Coronary Events) score variables was used. RESULTS Censoring of cs-cTnI data below the LoD yielded weaker diagnostic information [area under the curve (AUC), 0.781; 95% CI, 0.731–0.831] regarding AMI compared to the hs-cTnI assay (AUC, 0.949; CI, 0.936–0.961). Use of our model to estimate cs-cTnI values below the LoD showed an AUC improvement to 0.921 (CI, 0.902–0.940). The cs-cTnI LoD concentration had a negative predictive value (NPV) of 0.950. An estimated concentration that was to be undercut by 25% of patients presenting with suspected AMI was associated with an improvement of the NPV to 0.979. CONCLUSIONS Estimation of values below the LoD of a cs-cTnI assay with this new approach improves the diagnostic performance in evaluation of patients with suspected AMI.
Published: 2015

48. Occurrence and prognostic impact of systemic inflammatory response syndrome in transfemoral and transapical aortic valve implantation with balloon- and self-expandable valves

Author: Stephan Fichtlscherer, Mirko Doss, Sameer Gafoor, Andreas M. Zeiher, Florian Seeger, Sohil Behjati, Horst Sievert, Ralf Lehmann, and Thomas Schwietz
Subjects: Male, Aortic valve, Cardiac Catheterization, medicine.medical_specialty, Balloon, Cohort Studies, Transcatheter Aortic Valve Replacement, Postoperative Complications, Risk Factors, Internal medicine, medicine, Humans, Thoracic Wall, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Incidence, Incidence (epidemiology), Mortality rate, Retrospective cohort study, Aortic Valve Stenosis, Prognosis, medicine.disease, Systemic Inflammatory Response Syndrome, Surgery, Femoral Artery, Systemic inflammatory response syndrome, Stenosis, Logistic Models, Treatment Outcome, medicine.anatomical_structure, Heart Valve Prosthesis, Aortic valve stenosis, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Transcatheter aortic valve implantation (TAVI) is an alternative therapeutic option for patients with severe aortic valve stenosis (AS) and elevated surgical risk. Previous studies have suggested that the occurrence of systemic inflammatory response syndrome (SIRS) in patients undergoing TAVI is associated with an unfavourable outcome. We sought to assess the impact of different interventional access routes (transapical [TA] vs. transfemoral [TF]) and valve types (Medtronic CoreValve® [CV] vs. Edwards SAPIEN XT® [ES]) on the incidence of SIRS. In addition, the prognostic value of SIRS was evaluated. Methods and results Between January 2009 and July 2011 a total of 192 (out of 228) consecutive patients with severe aortic stenosis underwent TAVI at the University Hospital Frankfurt and were included in the current retrospective analysis. SIRS criteria were evaluated within the first 48 hours after TAVI. SIRS was defined according to existing definitions of the ACCP/SCCM Consensus Conference. A total of 75 (39.1%) patients developed SIRS at some time during the first 48 hours following TAVI. The occurrence of SIRS was independent from access route (TA 42.3% vs. TF 37.0%; p=0.28) as well as from type of valve used (ES 42.5% vs. CV 32.3%; p=0.11). However, the occurrence of SIRS was associated with a more than twofold higher one-year mortality rate (21.3%) compared to patients without SIRS in the first 48 hours (5.3%; p=0.04). Conclusions The occurrence of SIRS in the first 48 hours post procedure is associated with impaired prognosis following TAVI, but is independent from the chosen valve type and access route.
Published: 2015

49. New potential diagnostic biomarkers for pulmonary hypertension

Author: Svenja L. Tiede, Henning Gall, Oliver Dörr, Marina dos Santos Guilherme, Christian Troidl, Christoph Liebetrau, Sandra Voss, Robert Voswinckel, Ralph T. Schermuly, Werner Seeger, Friedrich Grimminger, Andreas M. Zeiher, Stefanie Dimmeler, Helge Möllmann, Christian W. Hamm, Hossein Ardeschir Ghofrani, Holger M. Nef, and Epidemiology
Subjects: Pulmonary and Respiratory Medicine, Placental growth factor, Adult, Male, Vascular Endothelial Growth Factor A, Pathology, medicine.medical_specialty, Hypertension, Pulmonary, Hemodynamics, Blood Pressure, Kaplan-Meier Estimate, Pregnancy Proteins, Gastroenterology, Sensitivity and Specificity, chemistry.chemical_compound, Internal medicine, medicine, Humans, Associated Pulmonary Arterial Hypertension, Aged, Placenta Growth Factor, Proportional Hazards Models, Lung, Vascular Endothelial Growth Factor Receptor-1, business.industry, Middle Aged, medicine.disease, Pulmonary hypertension, Vascular endothelial growth factor, medicine.anatomical_structure, chemistry, Case-Control Studies, Multivariate Analysis, Pulmonary venous hypertension, Female, business, Tyrosine kinase, Biomarkers
Abstract: This study aimed to determine whether the vascular endothelial growth factor (VEGF) family members soluble VEGF receptor 1 (also called soluble fms-like tyrosine kinase 1 (sFlt-1)) and placental growth factor (PlGF) could be used as biomarkers for pulmonary hypertension (PH).Consecutive patients undergoing right heart catheterisation were enrolled (those with mean pulmonary arterial pressure ≥25 mmHg were classed as having PH; those with mean pulmonary arterial pressure In total, 247 patients with PH were enrolled: 62 with idiopathic pulmonary arterial hypertension (IPAH), 14 with associated pulmonary arterial hypertension (APAH), 21 with collagen vascular disease (CVD), 26 with pulmonary venous hypertension, 67 with lung disease-associated PH and 57 with chronic thromboembolic PH. The non-PH control group consisted of 40 patients. sFlt-1 plasma levels were significantly higher in patients with IPAH, APAH, CVD and lung disease-associated PHversuscontrols; PlGF levels were significantly higher in all PH groupsversuscontrols. The combination of sFlt-1 and PlGF resulted in a sensitivity of 83.7% with specificity of 100% for pulmonary arterial hypertension. There was no association between sFlt-1 or PlGF and haemodynamic parameters, 6-min walking distance or survival.In summary, PlGF and sFlt-1 are promising diagnostic biomarkers for PH.
Published: 2015

50. Longitudinal change instead of baseline testosterone predicts depressive symptoms

Author: Lars Pieper, Hendrik Lehnert, Winfried März, David Pittrow, Hanna Kische, Robin Haring, Sigmund Silber, Uwe Koch-Gromus, John Venz, G. K. Stalla, Hans-Ulrich Wittchen, Andreas M. Zeiher, and Jens Klotsche
Subjects: Adult, Male, medicine.medical_specialty, Inverse Association, Endocrinology, Diabetes and Metabolism, Sexual Behavior, Lower risk, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Sex hormone-binding globulin, Sex Factors, Internal medicine, Diabetes mellitus, Surveys and Questionnaires, medicine, Humans, Testosterone, Longitudinal Studies, Baseline (configuration management), Biological Psychiatry, Depression (differential diagnoses), Aged, Depressive Disorder, biology, Endocrine and Autonomic Systems, business.industry, Depression, Odds ratio, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Cross-Sectional Studies, biology.protein, Female, sense organs, business, 030217 neurology & neurosurgery, Forecasting
Abstract: Background The association between total testosterone (T) and depression mostly relies on single sex hormone assessment and remains inconclusive. Thus, we investigated the comparative predictive performance of baseline T and change in T with development of depressive symptoms and incident depressive episodes. Methods We used data from 6493 primary care patients (2653 men and 3840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including four-year follow-up, repeated immunoassay-based measurement of serum T and depressive symptoms assessed by the Depression Screening Questionnaire (DSQ). Cross-sectional and longitudinal associations of baseline T and one-year change in T with prevalent and incident depression were investigated using age- and multivariable-adjusted regression models. Results Baseline T showed no association with prevalent or incident depressive symptoms and episodes in both sexes. In men, a positive change in T (higher T at one-year follow-up compared to baseline) was associated with a lower burden of depressive symptoms (β-coefficient per unit change in T: −0.17; 95% CI: −0.31 to −0.04) and lower risk of incident depressive symptoms (odds ratio per unit change in T: 0.84; 95% CI: 0.72–0.98) at four-year follow-up. In women, the association of T change with incident depressive episodes was rendered non-significant after multivariable adjustment. Discussion The present study observed a sex-specific inverse association of T change, but not baseline T, with increased depressive symptom burden in men. Future studies should assess longitudinal changes in sex hormone status as predictor of adverse health outcomes related to low T.
Published: 2017

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