DEPARTMENT OF CARDIOVASCULAR RESEARCH - Mario Negri · Head Giovanna BALCONI, BSc. Laboratory of Cardiopulmonary Pathophysiology Head Giuseppe RISTAGNO, M.D., Ph.D. ... from Mar 2013

DEPARTMENT OF CARDIOVASCULAR RESEARCH

STAFF

Head Roberto LATINI, M.D.

Laboratory of Cardiovascular Clinical Pharmacology

Head Roberto LATINI, M.D.

Bio-imaging Unit Head Fabio FIORDALISO, Biol.Sci.D. Cardiovascular Endocrine Unit Head Serge MASSON, Ph.D. Tissue Culture Unit Head Giovanna BALCONI, BSc. Laboratory of Cardiopulmonary Pathophysiology

Head Giuseppe RISTAGNO, M.D., Ph.D. Laboratory of General Practice Research

Head Maria Carla RONCAGLIONI, Biol.Sci.D. Laboratory of Medical Statistics

Head Simona BARLERA, Dr.Sci.Pol., MSc. Laboratory of Clinical Drug Evaluation

Head Maria Grazia FRANZOSI, Biol.Sci.D.

Bioinformatics Unit Head Enrico NICOLIS

CURRICULA VITAE

Roberto Latini got his Medical Doctor degree in 1978 at the University of Milan. Education 1970-1978 University of Milan School of Medicine, degree in Medicine 1981-1983 Merck Sharp & Dohme International Fellow in Clinical Pharmacology. Cardiology Fellow, Stanford

University Medical Center, California, USA Main fields of activity Mechanisms of cardiac damage following ischemia, with focus on neurohumoral activation. Use of stem cells for cardiac repair. Biohumoral investigations within large scale clinical trials in heart failure and atrial fibrillation. Positions from Mar 2013 Director of the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario Negri",

Milan, Italy from 1991 Member of the Steering Committees of the randomized clinical trial: ALOFT, ValHeFT, GISSI-HF,

GISSI-AF, CandHeart, CYCLE, ICOS-ONE. from 1990 Head of the Cardiovascular Clinical Pharmacology Laboratory (Department of Cardiovascular

Research) Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy 1999-2009 Visiting Professor Dept of Medicine, New York Medical College, Valhalla, NY, USA 1981-1983 Cardiology Fellow (Dr. R. E. Kates, Laboratory) Stanford University Medical Center, CA, USA 1976-1981 Member of the Sub-Group RMs for Drugs (Community Bureau of Reference, Commission of the

European Communities) 1973-1990 Fellow at the Laboratory of Clinical Pharmacology of the Istituto di Ricerche Farmacologiche "Mario

Negri", Milano, Italy Selected publications

Latini R, Gullestad L, Masson S, Nymo SH , Ueland T, Cuccovillo I, Vårdal M , Bottazzi B, Mantovani A, Lucci D, Masuda N, Sudo Y, Wikstrand J, Tognoni G, Aukrust P, Tavazzi L, on behalf of the Investigators of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-Heart Failure (GISSI-HF) trial. Pentraxin-3 in chronic heart failure: the CORONA and GISSI-HF trials. Eur J Heart Fail 2012; 14. 992-999

Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, Latini R, Val-HeFT Investigators, GISSI-HF Investigators. Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure. Data from two large randomized clinical trials. Circulation 2012; 125: 280-288

Damman K, Masson S, Hillege HL, Voors AA, van Veldhuisen DJ, Rossignol P, Proietti G, Barbuzzi S, Nicolosi GL, Tavazzi L, Maggioni AP, Latini R. Tubular damage and worsening renal function in chronic heart failure. J Am Coll Cardiol HF 2013; 1: 417-424

Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L, ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. New Engl J Med 2014; 370: 1412-1421

Ristagno G, Latini R, Vaahersalo J, Masson S, Kurola J, Varpula T, Lucchetti J, Fracasso C, Guiso G, Montanelli A, Barlera S, Gobbi M, Tiainen M, Pettilä V, Skrifvars MB, FINNRESUSCI Investigators. Early activation of the kynurenine pathway predicts early death and long-term outcome in patients resuscitated from out-of-hospital cardiac arrest. J Am Heart Assoc 2014; 3: e001094

Cosmi F, Di Giulio P, Masson S, Finzi A, Marfisi RM, Cosmi D, Scarano M, Tognoni G, Maggioni AP, Porcu M, Boni S, Cutrupi G, Tavazzi L, Latini R, GISSI-HF Investigators. Regular wine consumption in chronic heart failure: impact on outcomes, quality of life and circulating biomarkers. Circ Heart Fail 2015; 8: 428-437

Simona Barlera got her degree in Political Science, area Statistics at the “Università degli Studi di Milano” in Milano in 1992, followed by a master in Medical Statistics at the London School of Hygiene and Tropical Medicine, “University of London” in 1998. Education and training 1987-1992 Degree in Political Sciences, course of studies Statistics, Università degli Studi di Milano, Milano

(Italy) 1993-1995 Post-degree Specialization in Pharmacological Research. School of Specialization in Pharmacological

Research of Lombardy Region, Milan 1997-1998 Master of Science in Medical Statistics at the London School of Hygiene and Tropical Medicine,

University of London, London. 1998-1999 Visiting Scientist in the Department of Statistical Genetics, Wellcome Trust Centre for Human

Genetics, University of Oxford (UK). Main fields of activity Methodology of Clinical Trials in the cardiovascular field. Preparation and viewing of research protocols, planning and conduct of statistical analyses and the reporting of findings on scientific journals. Genetic epidemiology: genome-wide strategies (linkage analysis) to identify susceptibility genes in coronary artery disease; case-control studies in order to identify candidate genes involved in the cardiovascular pathology. Position Held 2014 Member of the organizing committee for the Master of Science in Clinical Research, Department of

Pathophysiology and Transplantation, University of Milan.

2014 Member of the Scientific Committee for the Consensus Conference on Closing of Abdomen Complex (ACOI)

2013 Member of the Scientific Committee for the Consensus Conference on Laparoscopic cholecystectomy (ACOI)

2012 Member of the Scientific Committee for the Consensus Conference on Surgery of Rectal Cancer (ACOI)

from Oct 2006 Head of the Laboratory of Medical Statistics, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy

1999 -2006 Head of the Medical Statistics Unit, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy

1992-1997 Researcher in the Unit of Applied Statistics and Information Technology, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy

Selected publications

Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) Lipoprotein Level and Coronary Disease. N Engl J Med 2009; 361: 2518-2528

GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360: 1606-1617

Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011; 43: 339-344

Barlera S, Tavazzi L, Franzosi MG, Marchioli R, Raimondi E, Masson S, Urso R, Lucci D, Nicolosi GL, Maggioni AP, Tognoni G, on behalf of the GISSI-HF Investigators. Predictors of mortality in 6975 patients with chronic heart failure in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure Trial. Proposal for a Nomogram. Circ Heart Fail 2013; 6: 31-39


Rossignol P, Masson S, Barlera S, Girerd N, Castelnovo A, Zannad F, Clemenza F, Tognoni G, Anand IS, Cohn JN, Anker SD, Tavazzi L, Latini R, GISSI-HF Investigators, Val-HeFT Investigators. Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights From GISSI-HF and Val-HeFT Trials. Eur J Heart Fail 2015; 17: 424-433

Maria Grazia Franzosi got her Biological Science degree in 1972 at the University of Milan. Education 1972 Doctoral degree in Biological Sciences, University of Milan, Italy 1978 Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche "Mario Negri” di

Milano, Italy Main fields of activity Coordination of multicentric randomised clinical trials. Relationship between genetic and environmental risk factors in coronary events. Pharmacogenetics. Cardiovascular genetic epidemiology. Pharmacoeconomics. Drug Epidemiology and Post-Marketing Surveillance. Position from 2002 to Feb 2013 Director of the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche

"Mario Negri", Milano, Italy from 2005 Member of the Coordinating Committee of Master course in Clinical Research - University of

Milano from 2004 Member of Steering Committee, Studio GISSI-AF Study, Milano, Italy from 2001 Member of Steering Committee, Studio GISSI-HF Study, Milano, Italy from 1998 Member of Steering Committee of the PROCARDIS Research Programme - A genome-wide

strategy to identify susceptibility loci in precocious coronary artery disease - University of Oxford, UK

from 1997 Member of “Antithrombotic Trialists’ Collaboration”, Oxford, UK from 1996 Member of Steering Committee e National Coordinator for Italy of the Organization to Assess

Strategies for Ischemic Syndromes (OASIS-2, OASIS-4 CURE, Michelangelo OASIS-5 e OASIS 6, CURRENT OASIS-7, FUTURA OASIS-8), INTER-HEART, ACTIVE, RE-LY, ACTIVE, RE-LY, AVERROES, RE-LY Registry, RIVAL, MANAGE, Population Health Research Institue, McMaster University, Hamilton, Canada

1994-1996 Director of European Coordinating Centre and Member of Steering Committee, Collaborative Organization for RheothRx Evaluation (CORE), McMaster University, Hamilton, Canada

from 1993 Member of Steering Committee, Studio GISSI-Prevenzione, Milano, Italy from 2002 Member of “Fibrinolytic Therapy Trialists’s Collaboration”, Oxford, UK e del “Collaborative

Group on Angiotensin Converting Enzyme Inhibitors Trials”, National Institutes of Health, Bethesda, Washington, USA

from 1989 Head of the Laboratory of Clinical Drug Evaluation, Istituto di Ricerche Farmacologiche "Mario Negri"

1985-1988 Head of the Clinical Drug Evaluation Unit of the Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negri"

from 1984 Member of the Scientific and Organising Secretariat, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-1, GISSI-2, GISSI-3 studies) Milano, Italy

1975-1984 Researcher at the Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negri" and at the Regional Center for Drug Information of the Lombardy Region

Selected publications

Franzosi MG. Should we continue to use BMI as a cardiovascular risk factor? Lancet 2006; 368: 624-625 Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A,

Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528

Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ, on behalf of the RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983

Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011; 43: 339-344

Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d'Arienzo C, Fanelli R, Garlanda C, Gori F, Mango R, Mantovani A, Merla G, Nicolis EB, Pietri S, Presbitero P, Sudo Y, Villella A, Franzosi MG. Influence of pentraxin 3 (PTX3) genetic variants on myocardial Infarction risk and PTX3 plasma levels. PLoS One 2012; 7: e53030

Hohnloser SH, Shestakovska O, Eikelboom J, Franzosi MG, Tan RS, Zhu J, Yusuf S, Connolly SJ.The effects of apixaban on hospitalizations in patients with different types of atrial fibrillation: insights from the AVERROES trial. Eur Heart J 2013; 34: 2752–2759

Giuseppe Ristagno got his Medical Doctor degree in 2003 at the University of Palermo. Education 1998-2003 Degree in Medicine and Surgery, University of Palermo 2003-2007 Residency in Anesthesia and Intensive Care, University of Trieste 2005-2007 Fellowship in Critical Care Medicine, Weil Institute of Critical Care Medicine, California, USA 2009-2013 PhD in “Life and Biomolecular Sciences”, Open University, Milton Keynes, UK Main fields of activity Mechanisms of cardiac and cerebral injury canismi after myocardial infarction and cardiac arrest. Research on new therapeutic approaches to improve cardiac and cerebral outcome after cardiac arrest in rodent and porcine models. Development of new defibrillation techniques. Research on new biomarkers predictive of outcome after cardiac arrest. Positions from Ott 2015 Head of the Laboratory of Cardiopulmonary Pathophysiology, IRCCS-Istituto di Ricerche

Farmacologiche “Mario Negri”, Milano from Feb 2015 Member of the “European Resuscitation Council” writing group, Basic Life Support Task Force froml 2013 Coordinator of the Italian Resuscitation Council Scientific Committe from 2013 Member of the Board of Società Italiana Terapia Intensiva from Ott 2013 Member of the Steering Committee and Sceintific Committe of “Shockomics Consortium:

Multiscale approach to the identification of molecular biomarkers in acute heart failure induced by shock”

from 2012 Member of the “European Resuscitation Council” BLS working group from Nov 2012 Member of the GdS area Emergenze, Società Italiana Anestesia Analgesia Rianimazione Terapia

Intensiva 2009-2015 Researcher at the Clinical Cardiovascular Pharmacology Lab, IRCCS-Istituto di Ricerche

Farmacologiche “Mario Negri”, Milano 2008-2012 Assistant Professor, Weil Institute of Critical Care Medicine, Rancho Mirage, California Selected publications

Fumagalli F, Russo I, Staszewsky L, Li Y, Letizia T, Masson S, Novelli D, Rocchetti M, Canovi M, Veglianese P, Gobbi M, Latini R, Zaza A, Ristagno G. Ranolazine ameliorates post-resuscitation electrical instability and myocardial dysfunction and improves survival with good neurological recovery in a rat model of cardiac arrest. Heart Rhythm 2014; 11: 1641-1647

Ristagno G, Fumagalli F, Russo I, Tantillo S, Zani DD, Locatelli V, De Maglie M, Novelli D, Staszewsky L, Vago T, Belloli A, Di Giancamillo M, Fries M, Masson S, Scanziani E, Latini R. Post-resuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest. Shock 2014; 41: 72-78


He M, Gong Y, Li Y, Mauri T, Fumagalli F, Bozzola M, Cesana G, Latini R, Pesenti A, Ristagno G. Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests. Crit Care 2015; 19: 425

Ristagno G, Latini R, Plebani M, Zaninotto M, Vaahersalo J, Masson S, Tiainen M, Kurola J, Gaspari F, Milani V, Pettilä V, Skrifvars MB; FINNRESUSCI Study Group. Copeptin levels are associated with organ dysfunction and death in the intensive care unit after out-of-

hospital cardiac arrest. Crit Care 2015; 19: 132 Ristagno G, Mauri T, Cesana G, Li Y, Finzi A, Fumagalli F, Rossi G, Grieco N, Migliori M, Andreassi A, Latini R, Fornari C, Pesenti A;

Azienda Regionale Emergenza Urgenza (AREU) Research Group. Amplitude Spectrum Area to Guide Defibrillation: A Validation on 1617 Ventricular Fibrillation Patients. Circulation 2015; 131: 478-487

Maria Carla Roncaglioni got her Biological Science degree in 1987 at the University of Milan. Education 1987 Doctoral degree in Biological Sciences, University of Milan, Italy 1982-1983 “Research Fellow” at the Dept. of Biochemistry, Faculty of Medicine, Rijksuniversiteit of Limburg,

Maastricht , The Netherland (Prof. C.Hemker); 1998-1999 “Visiting Scientist” at the Cardiovascular Research Unit, Hammersmith Hospital, London, UK (Prof. A.

Maseri) Main fields of activity Coordination of multicenter clinical trials and observational studies in different cardiovascular areas (neurological, angiological, cardiological). Coordination of a network of more than 1000 GPs actively involved in epidemiological and experimental studies in the prevention of cardiovascular diseases. Position from 2001 Head of the Laboratory for General Practice Research, Istituto di Ricerche Farmacologiche "Mario Negri",

Milano, Italy from 1989 Senior Researcher in the Clinical Pharmacology Laboratory, Istituto di Ricerche Farmacologiche "Mario

Negri", Milano, Italy from 1974 Researcher in the Laboratory for the Study of Haemostasis and Thrombosis, Istituto di Ricerche

Farmacologiche "Mario Negri", Milano, Italy Selected publications

Tognoni G, Avanzini F, Pangrazzi J, Roncaglioni M C, Bertele V, de Gaetano G, Caimi V, Tombesi M, Colombo Fabio, Barlera S, PPP - Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: A randomized trial in general practice. Lancet 2001; 357: 89-95

Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi J, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295: 306-313

Montalvo G, Avanzini F, Anselmi M, Prandi R, Ibarra S, Marquez M, Armani D, Moreira J M, Caicedo C, Roncaglioni MC, Colombo Fabio, Camisasca P, Milani V, Quimi' S, Gonzabay F, Tognoni G. Diagnostic evaluation of people with hypertension in low income country: cohort study of "essential" method of risk stratification. BMJ 2008; 337: a1387

Rothwell PM, Price JF, Fowkes FGR , Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M, Mehta Z, Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012; 379: 1602-1612

Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V. Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013; 368: 1800-1808

Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernández-Ortiz A, Alvarez L, Guzmán L , Linares JC, Garcia F, D'Aniello F, Arnáiz JA , Varea S, Martínez F, Lorenzatti A, Imaz I, Sánchez-Gómez LM, Roncaglioni MC, Baviera M, Smith SC, Taubert K , Pocock S, Brotons C, Farkouh ME, Fuster V. A polypill strategy to improve adherence. Results from the FOCUS Project. J Am Coll Cardiol 2014; 64: 2071-2082

Giovanna Balconi got her degree at the School for Technicians of Biomedical Institutes of the University of Milan, with a specialisation in Histology in the Pathological Anatomy Laboratory of the same University (1968). Main fields of interest Isolation, culture and characterization of peripheral blood circulating progenitor cells of patients with heart failure. “In vitro” culture and characterization of stem cells for repair of myocardial infarction in experimental animal models. Management of biobanks in clinical studies. Positions from July 2005 Head of Tissue Culture Unit, Cardiovascular Clinical Pharmacology Laboratory, Istituto di

Ricerche Farmacologiche "Mario Negri", Milano, Italy Oct 1995 - June 2005 Head of Tissue Culture Unit, Vascular Biology Laboratory, Istituto di Ricerche

Farmacologiche "Mario Negri", Milano, Italy Dec 1983 - Oct 1995 Head of Tissue Culture Unit, Anticancer Chemotherapy Laboratory, Istituto di Ricerche

Farmacologiche "Mario Negri", Milano, Italy Oct 1968 - Nov 1983 Researcher, Anticancer Chemotherapy Laboratory, Istituto di Ricerche Farmacologiche "Mario

Negri", Milano, Italy Selected publications

Cusella De Angelis MG, Balconi G, Bernasconi S, Zanetta L, Boratto R, Galli D, Dejana E, Cossu G. Skeletal myogenic progenitors in the endothelium of lung and yolk sac. Exp Cell Res 2003; 290: 207-216

Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F, Chimenti S, Cusella G, Dejana E, Cossu G, Latini R. Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular

mechanisms. A comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arterioscler Thromb Vasc Biol 2005; 25: 692-697

Sarto P, Balducci E, Balconi G, Fiordaliso F, Merlo L, Tuzzato G, Pappagallo GL, Frigato N, Zanocco A, Forestieri C, Azzarello G, Mazzucco A, Valenti M T, Alborino F, Noventa D, Vinante O, Pascotto P, Sartore S, Dejana E, Latini R. Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure. J Card Fail 2007; 13: 701-708

Galvez BG, Sampaolesi M, Barbuti A, Crespi A, Covarello D, Brunelli S, Dellavalle A, Crippa S, Balconi G, Cuccovillo I, Molla F, Staszewsky L, Latini R, DiFrancesco D, Cossu G. Cardiac mesoangioblasts are committed, self-renewable progenitors, associated with small vessels of juvenile mouse ventricle. Cell Death Differ 2008; 15: 1417-1428

Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L, Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulating pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure. J Cardiac Fail 2009; 15: 747-755

Raimondi MT, Balconi G, Boschetti F, Di Metri A, Mohammed SAA, Quaglini V, Araneo L, Galvez BG, Lupi M, Latini R, Remuzzi A. An opto-structural methods to estimate the stress-strain field induced by cell contraction on substrates of controlled stiffness in vitro. J Appl Biomater Function Mater 2013; 11: 143-150

Fabio Fiordaliso got his Biological Science degree in 1995 at the University of Milan. Education 1998 Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche “Mario Negri”,

Milan, Italy 1995 Doctoral degree in Biological Sciences, University of Milan, Italy Main fields of activity Morphological and structural analysis of cells and tissue by optical, confocal and transmission electron microscopy, focusing on the mechanism of internalization and intracellular localization of nanoparticles for therapeutic use. Positions from 2007 Head of Bio-imaging Unit, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche

“Mario Negri”, Milan from 2006 Member of the Heart Failure Association (HFA) of the European Society of Cardiology from 2005 Member of the Working group on myocardial function (WG 4) of the European Society of Cardiology from 2005 Member of the steering committee of the Consorzio of Microscopy and Image Analysis (MIA) from 2001 Senior Research Scientist, Laboratory of Cardiovascular Clinical Pharmacology (Department of

Cardiovascular Research), Istituto di Ricerche Farmacologiche “Mario Negri”, Milan 1997-2001 Post-Doctoral Research Fellow at Cardiovascular Research Institute (Department of Medicine), New York

Medical College, Valhalla, New York 1994-1997 Research Fellow, Laboratory of Cardiovascular Clinical Pharmacology (Department of Cardiovascular

Research), Istituto di Ricerche Farmacologiche “Mario Negri”, Milan 1992-1994 Research training, Institute of General Pathology, University of Milan (Italy) Selected publications

Fiordaliso F, De Angelis N, Cuccovillo I, Bai A, Salio M, Serra DM, Bianchi R, Razzetti R, Latini R, Masson S. Effect of β-adrenergic and renin-angiotensin system blockade on myocyte apoptosis and oxidative stress in diabetic hypertensive rats. Life Sci 2007; 81: 951-959

Basso M, Pozzi S, Tortarolo M, Fiordaliso F, Bisighini C, Pasetto L, Spaltro G, Lidonnici D, Gensano F, Battaglia E, Bendotti C, Bonetto V. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem 2013; 288: 15699-15711

Papa S, Rossi F, Ferrari R, Mariani A, De Paola M, Caron I, Fiordaliso F, Bisighini C, Sammali E, Colombo C, Gobbi M, Canovi M, Lucchetti J, Peviani M, Morbidelli M, Forloni G, Perale G, Moscatelli D, Veglianese P. Selective nanovector mediated treatment of activated proinflammatory microglia/macrophage in spinal cord injury. ACS Nano 2013; 7: 9881-9895

Balducci C, Mancini S, Minniti S, La Vitola P, Zotti M, Sancini G, Mauri M, Cagnotto A, Colombo L, Fiordaliso F, Grigoli E, Salmona M, Snellman A, Haaparanta-Solin M, Forloni G, Masserini M, Re F. Multi-functional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models. J Neurosci 2014; 34: 14022-14031

Bigini P, Previdi S, Casarin E, Silvestri D, Violatto MB, Facchin S, Sitia L, Rosato A, Zuccolotto G, Realdon N, Fiordaliso F, Salmona M, Morpurgo M. In vivo fate of avidin-nucleic acid nanoassemblies as multifunctional diagnostic tools. ACS Nano 2014; 8: 175-187

Bouybayoune I, Mantovani S, Del Gallo F, Bertani I, Restelli E, Tapella L, Comerio L, Bianchi S, Fernández-Borges N, Mangieri M, Bisighini C, Galina V. Beznoussenko G, Paladini A, Balducci C, Micotti E, Forloni G, Castilla J, Fiordaliso F, Tagliavini F, Imeri L, Chiesa R. Transgenic fatal familial insomnia mice indicate prion-independent mechanisms of pathogenesis and phenotypic expression of disease. PLoS Pathog 2015; 11: e1005046

Serge Masson obtained his doctorate (PhD) in Biochemistry and Cellular Biology in 1990 at the University of Marseilles (France), followed by a postdoctoral stay at the Panum Institute in Copenhagen (Denmark). Education 1988-1990 Doctorate fellow, Faculty of Medicine, University of Aix-Marseilles, France 1990-1993 Post-doctoral Researcher, Panum Institute and Assistant Lecturer, University of Copenhagen, Denmark 1993 Research Scientist, NMR Laboratory, Hospital “San Raffaele”, Milan, Italy from 1994 Research Scientist, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario

Negri", Milano, Italy Main fields of activity Physiopathology, diagnostic and prognostic role of the activation of neuroendocrine systems in cardiovascular disease

Position from 2002 Head of the Cardiovascular Endocrine Unit, responsible for Quality Assurance for the Department of

Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy from 2011 Thesis Examiner for PhD of the Open Univerisity of London, UK from 2002 Tutor of fellows of the School of Specialists in Pharmacological Research, Istituto di Ricerche

Farmacologiche "Mario Negri", Milano, Italy from 2002 Fellows of the American Heart Association (Basic Council) and the Working Group on Myocardial

Function of the European Society of Cardiology Selected publications

Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, Latini R, Val-HeFT Investigators, GISSI-HF Investigators. Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure. Data from two large randomized clinical trials. Circulation 2012; 125: 280-288

Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L, ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370: 1412-1421

Cosmi F, Di Giulio P, Masson S, Finzi A, Marfisi RM, Cosmi D, Scarano M, Tognoni G, Maggioni AP, Porcu M, Boni S, Cutrupi G, Tavazzi L, Latini R, GISSI-HF Investigators. Regular wine consumption in chronic heart failure: impact on outcomes, quality of life and circulating biomarkers. Circ Heart Fail 2015; 8: 428-437

Masson S, Agabiti N, Vago T, Miceli M, Mayer F, Letizia T, Wienhues-Thelen U, Mureddu GF, Davoli M, Boccanelli A, Latini R, PREDICTOR Study Group. The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk. J Intern Med 2015; 277: 318-330

Masson S, Caironi P, Fanizza C, Thomae R, Bernasconi R, Noto A, Oggioni R, Pasetti GS, Romero M, Tognoni G, Latini R, Gattinoni L, ALBIOS Study Investigators. Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. Intensive Care Med 2015; 41: 12-20

Masson S, Wu JHY, Simon C, Barlera S, Marchioli R, Mariani J, Macchia A, Lombardi F, Vago T, Aleksova A, Dreas L, Favaloro RR, Hershson AR, Puskas J D, Dozza L, Silletta M G, Tognoni G, Mozaffarian D, Latini R, OPERA Investigators. Circulating cardiac biomarkers and postoperative atrialfibrillation in the OPERA trial. Eur J Clin Invest 2015; 45: 170-178

Enrico Bjørn Nicolis has attended the courses in Computer Science at the University of Milan. Education 1991-1999 “Research fellow”, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy Main fields of activity Data management and analysis of randomized clinical trials. Developing of database and tools for studies of population genetics, particularly for linkage analysis. Position from 2001 Head of the Bioinformatics Unit, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy from 1999 Research fellow of the Laboratory of Clinical Drugs Evaluation from 1997 System administrator at the EDP center, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy from 1991 Research fellow at the Medical Informatics and Applied Statistics Unit, Istituto di Ricerche

Farmacologiche "Mario Negri", Milano, Italy Selected publications

Santoro E, Nicolis E, Franzosi MG.Telecommunication technology for the management of large scale clinical trials: The GISSI experience. Comput Methods Programs Biomed 1999; 60: 215-223

Specchia C, Barlera S, Chiodini BD, Nicolis EB, Farrall M, Peden J, Collins R, Watkins H, Tognoni G, Franzosi MG, PROCARDIS Consortium. Quantitative trait genetic linkage analysis of body-mass index in familial coronary artery disease. Hum Hered 2008; 66: 19-24

Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d'Arienzo C, Fanelli R, Garlanda C, Gori F, Mango R, Mantovani A, Merla G, Nicolis EB, Pietri S, Presbitero P, Sudo Y, Villella A, Franzosi MG. Influence of pentraxin 3 (PTX3) genetic variants on myocardial Infarction risk and PTX3 plasma levels. PLoS One 2012; 7: e53030

Ohmann C, Canham S, Cornu C, Dreß J, Gueyffier F, Kuchinke W, Nicolis EB, Wittenberg M. Revising the ECRIN standard requirements for information technology and data management in clinical trials. Trials 2013; 14: 97

Pileggi S, Barlera S, Nicolis E, Crociati L, Pietri S, Specchia C, Franzosi MG. Association of ADIPOQ variants and heart failure in an Italian population. Ther Adv Cardiovasc Dis. 2014; 8: 89-96.

Parolo S, Lisa A, Gentilini D, Di Blasio A M, Barlera S, Nicolis EB, Boncoraglio GB, Parati EA, Bione S. Characterization of the biological processes shaping the genetic structure of the Italian population. BMC Genet 2015; 16: 132

ACTIVITIES The areas of interest of the Department of Cardiovascular Research include the experimental, clinical, genetic, epidemiological aspects of acute myocardial infarction, cardiac failure, cardiac arrhythmias, cardiac arrest, as well as the clinical and epidemiological investigation of cardiovascular prevention, hypertension and stroke. Following the successful experience of the GISSI-trials (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto), the activation of large collaborative networks in the setting of the National Health Service hospitals and in general practice has become a key characteristic of the Department, which

can now rely on the permanent collaboration of over 300 clinical groups and of several hundred general practitioners. Over the years, firm links have also been established with international leading research groups. The activity in experimental translational research includes the pathophysiology, the pharmacological modulation and the prognostic role of the activation of the renin-angiotensin-aldosterone system, as well as other biohumoral systems, in myocardial infarction and heart failure. A model of cardiac arrest and cardiopulmonary resuscitation in rats and pigs has been recently set up and is being used for assessing the role of inflammation in cardiac and brain injury after cardiac arrest, and the protective effects of different interventions. The activity in clinical research includes the clinical assessment of therapeutic strategies and of biomarkers of cardiovascular risk within clinical trials in the field of acute coronary syndromes, congestive heart failure and atrial fibrillation. Several studies have been conducted in the area of clinical epidemiology and risk factors assessment of myocardial infarction. The collaboration with an european genetic network has allowed the participation to large GWAS (genome wide association studies) on coronary disease, myocardial infarction and stroke. The collaboration with a large network of General Practitioners in the area of cardiovascular prevention allowed to test new hypotheses through large scale clinical trials and to evaluate the actual transferability of evidence based interventions in the everyday practice through epidemiological or outcome research studies. Among the different activities, the Cardiovascular Research Department contributed to the accreditation of the Institute as a Contract Research Organization (CRO) for the conduction of clinical trials, mainly academic. The Department is able to arrange monitoring activities (counting on certified monitoring personnel) and it is also attested by Eudravigilance for the sumbission of online Safety Reports. Pharmacoepidemiological studies through the analysis of a large sample of Local Health Units drug prescriptions were also performed. A research network of nurses has been developed with the main focus on the assessment of health-related quality of life of patients and on the epidemiology of nursing interventions and their implications for patients' well being and outcomes. Participation to public ongoing projects funded on a competitive basis: 1. European projects (FP7):

- FOCUS - HOMAGE - CREACTIVE - SHOCKOMICS

2. European projects (Horizon 2020- PHC-17-2014 - Call: “Comparing the effectiveness of existing health care interventions in the elderly): - SECURE

3. Projects by the Italian Ministry of Health, Ricerca Finalizzata: - ICOS-ONE (call 2009)

- Immune procoagulant and inflammatory responses in severe sepsis and septic shock (call 2011-2012) - Preclinical optimization of treatment with inhaled argon to improve neurological outcome and survival

after cardiac arrest (Young Investigators call 2011-2012) 4. Agenzia Italiana del Farmaco AIFA Ricerca Indipendente sui Farmaci (Bando AIFA 2008 -

FARM8PRTEC): - Studio BeTACTIC - Studio multicentrico, prospettico, randomizzato, in aperto, di confronto

dell'efficacia di Everolimus e Micofenolato in associazione con Ciclosporina in pazienti con rigetto cronico dopo trapianto di cuore - BeTACTIC (Best Therapy After Cardiac Transplantation, the Italian Challenge)

MAIN FINDINGS Experiments are ongoing on the cardio- and neuro-protective effects of the noble gas argon, administered after cardiac arrest. Preliminary results of experiments in the pig suggest that ventilation with argon 70% in oxygen started with the resuscitation manoeuvers improves the recovery of neurologic functions and reduces histological injury in the brain and in the heart. One of the causes of the low survival of patients resuscitated from cardiac arrest is the lack of knowledge in the mechanisms involved in organ damage after cardiac arrest. We used experimental models of cardiac

arrest and resuscitation in rats and in pigs to study these mechanisms. We have found that, after cardiac arrest and resuscitation, the catabolism of the essential aminoacid tryptophan is importantly activated through the kynurenine pathway. Tryptophan is an aminoacid introduced in our body through the diet and is important for the synthesis of serotonin and vitamins of the B group. The catabolism of tryptophan into kynurenine observed in our experiments has also been confirmed in a small cohort of 7 patients resuscitated from cardiac arrest then confirmed in 245 patients from the. large cohort of the FINNRESUSCI study, one of the most comprehensive European biobanks. This biobank collects the plasma samples from more than 300 patients resuscitated from cardiac arrest in Finland, and hospitalized in one of the 21 intensive care units in the country. FINNRESUSCI also collects data about the rescue time, therapy, intra-hospital outcome, and 1 year survival with neurological recovery. The degradation of tryptophan was activated within a few hours after resuscitation, and depended on the duration of cardiac arrest, the type of cardiac arrest and the necessity of the use of vasopressors for resuscitation, such as adrenaline. Furthermore the activation of the degradation of tryptophan was directly related to the severity of cardiac dysfunction and hemodynamic alterations observed after resuscitation. Finally, we demonstrated that the extent of degradation of tryptophan was a predictive factor of early death in ICU and 1-year outcome. The early use of a defibrillator is, along with chest compressions, the only intervention able to restore spontaneous circulation and to improve survival in victims of cardiac arrest caused by ventricular fibrillation. However, timing of defibrillation in relationship to chest compression is a subject of major interest because it is difficult to determine the priority of intervention once rescuer arrives at the cardiac arrest scene, namely chest compression or defibrillation first. Indeed, there are no parameters available that allow the rescuer to determine whether it is more effective to perform chest compression or electrical defibrillation as initial treatment. The real-time analysis of the electric waveform of ventricular fibrillation seems to be an useful and non-invasive way to set a strategy for successful resuscitation. In particular, the algorithm that enables the spectral analysis of the ventricular fibrillation waveform, generates a value, called AMSA, that represents one of the most accurate predictor of the success of defibrillation. After the study performed with the collaboration of most of the 118 systems in Lombardia Region on cardiac arrest patients resuscitated from 2008 to 2010, a prospective trial is being designed ot verify whether the use of AMSA will improve the outcomes of patients resuscitated after cardiac arrest. The Department has contributed to the largest GWAS study of ischemic stroke conducted to date, as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). A new association with the HDAC9 gene region has been identified in large vessel stroke with an estimated effect size that is at the larger end for GWAS loci (OR = 1.38, 95% CI = 1.22–1.57, from replication data). The GWAS also replicated known associations with three other loci and showed genetic heterogeneity across subtypes of the disease for all four stroke loci. This genetic heterogeneity seems likely to reflect heterogeneity in the underlying pathogenic mechanisms and reinforces the need for the consideration of stroke subtypes separately in research and clinical contexts. After publication of the results of the FOCUS study (Fixed Dose Combination Drug for Secondary Prevention), (J Am Coll Cardiol 2014; 64: 2071-2082) the Laboratory of Research in General Medicine is participating to a new EU funded project, a Phase 3 trial on polypill, SECURE.

NATIONAL COLLABORATIONS ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri) AREU - Azienda Regionale Emergenza Urgenza - Lombardia Azienda Ospedaliera S Croce e Carle, Cuneo CDI - Centro Diagnostico Italiano Spa, Milano Centro Cardiologico Monzino IRCCS, Milano Centro Emofilia e Trombosi Angelo Bianchi Bonomi, Fondazione Ca' Granda - Ospedale Maggiore Policlinico, Milano CINECA (Consorzio Interuniversitario per il Calcolo Automatico dell'Italia Nord-Orientale) CSeRMEG (Centro Studi e Ricerche in Medicina Generale) Dipartimento Cardio-Vascolare ed Endocrino-Metabolico, Ospedale Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo (FG) Dipartimento Cardiologico “A. De Gasperis” - Struttura Complessa di Cardiologia 2 - Insufficienza Cardiaca e Trapianto, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milano Dipartimento di Cardiologia e UTIC, Istituto Clinico Humanitas IRCCS, Rozzano (MI)

Dipartimento di Immunologia, Istituto Clinico Humanitas IRCCS, Rozzano (MI) Fondazione Associazione Medici Diabetologi AMD, Centro Studi e Ricerche Onlus, Roma Fondazione Filarete, Milano Fondazione Istituto Neurologico “Carlo Besta”, Milano Fondazione per il Tuo Cuore - Heart Care Foundation - ONLUS, Firenze Fondazione Sestini, Bergamo Gruppi organizzati di MMG (FIMMG, CoS, Ass.Cu.M.I., AMISI) IEO - Istituto Europeo di Oncologia, Milano IFOM-FIRC, Milano IRC - Italian Resuscitation Council, Bologna ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo Istituto di Anestesiologia e Rianimazione, IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Milano Istituto Auxologico Italiano IRCCS Milano Istituto di Anestesia e Rianimazione, Ospedale San Gerardo, Monza (MI) Istituto di Ricerca in Cure palliative Lino Maestroni, Cremona Istituto Ortopedico Galeazzi, Milano Istituto Ortopedico Rizzoli, Bologna IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milano Laboratorio di Endocrinologia, Ospedale Luigi Sacco, Milano PoliMi Politecnico, Milano Provincia Autonoma di Trento Regione Emilia Romagna Regione Lombardia Regione Lazio, Dipartimento di Epidemiologia Regione Puglia, Agenzia Regionale Sanitaria Servizio Farmaceutico, USSL 20, Verona SIBioC (Società Italiana di Biochimica Clinica e Biologia Molecolare) Unità Operativa Piede Diabetico, IRCCS Multimedica, Sesto San Giovanni (MI) Università degli Studi di Bari, Aldo Moro, Dipartimento di Scienze Biomediche e Oncologia Umana Università degli Studi di Catania, Dipartimento di Anestesia e Terapia Intensiva Università degli Studi di Catania, Dipartimento di Scienze del Farmaco, Sezione di Biochimica Università degli Studi di Milano, Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti Università degli Studi di Milano, Dipartimento di Medicina Interna Università degli Studi di Milano, Dipartimento di Scienze Farmacologiche Università degli Studi di Milano, Polo Veterinario di Lodi (MI) Università degli Studi di Milano Bicocca, Dipartimento di Biotecnologie e Bioscienze Università degli Studi di Milano Bicocca, Dipartimento di Scienze della Salute, Centro di Biostatistica per l’Epidemiologia Clinica Università degli Studi di Palermo, Scuola di Specializzazione in Anestesia e Rianimazione Università degli Studi di Parma, Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali Università degli Studi di Torino, Dipartimento di Anatomia, Farmacologia e Medicina Forense Università degli Studi di Torino, Dipartimento di Scienze della Sanità Pubblica e Pediatriche Università degli Studi di Verona, Dipartimento di Sanità Pubblica

INTERNATIONAL COLLABORATIONS Cecomet (Centro de Epidemiologia comunitaria y Medicina tropical, Esmeraldas) Ecuador Cochrane Collaboration, Oxford, UK Clinical Trial Research Unit, Auckland University, Nuova Zelanda CNIC Centro Nacional de Investigaciones Cardiovasculares, Madrid , Spain CTSU (Clinical Trial Service Unit) /ISIS (International Studies on Infarct Survival), Oxford, UK Department of Cardiology, Italian Hospital of Buenos Aires, Argentina Department of Communications Engineering, Universidad de Pais Vasco, Bilbao, Spain

Department of Epidemiology, Harvard School of Public Health, Boston, USA Department of Intensive Care, Erasme Hospital, Brussels, Belgium DSAN SUPSI (Scuola Universitaria Professioni Sanitarie), Lugano, Switzerland ECLA (Estudios Cardiologicos de Latino-America) ECRIN (European Clinical Research Infrastructures Network) ERC (European Resuscitation Council), Basic Life Support Working group Helsingborg Hospital, Sweden ILCOR (International Liaison Committee on Resuscitation), Task Force for Cardiopulmonary Resuscitation 2015 International Guidelines Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, Vandoeuvre-les-Nancy, France ISMMS Icahn School of Medicine at Mount Sinai, New York, USA, Karolinska Institutet, Stockholm, Sweden Laerdal Foundation for Acute Medicine, Stavanger, Norway Mayo Clinic, Cardiorenal Research Lab, Rochester, MN, USA PHRI (Population Health Research Institute), McMaster University, Hamilton, Ontario, Canada The Third Military University, Chong Qing, China University of Cambridge, UK University of Aachen, Germany University of Helsinki, Central Hospital, Finland University of Manchester, Medicine/Cardiology Manchester Royal Infirmary, UK University of Oslo, Division of Medicine, Akershus University Hospital, Norway University Medical Center, Groningen, The Netherlands University Medical Center, Maastricht, The Netherlands Wellcome Trust Centre for Human Genetics, University of Oxford, UK WONCA (World Organization of Family Doctors)

EDITORIAL BOARD MEMBERSHIP Assistenza Infermieristica e Ricerca, European Journal of Oncology Nursing, International Journal of Practice Development (Paola Di Giulio) European Journal Heart Failure (Simona Barlera) Current Controlled Trials, Global Heart (Maria Grazia Franzosi) European Journal Heart Failure, Journal of Cardiac Failure, Journal of Cardiovascular Medicine (Roberto Latini) Disease Markers (Serge Masson) Open Access Critical Care, The Scientific World Journal (Giuseppe Ristagno) European Heart Journal, International Journal of Health Services, Journal of Cardiovascular Medicine (Gianni Tognoni)

PEER REVIEW ACTIVITIES American Heart Journal, American Journal of Cardiology, American Journal of Hypertension, American Journal of Medicine, Annali di Igiene, Archives of Medical Research, Atherosclerosis Thrombosis and Vascular Biology, Biomarkers in Medicine, BMC Cardiovascular Disorders, BMJ Open, Canadian Journal of Physiology and Pharmacology, Canadian Medical Association Journal, Cardiology, Cardiology Research and Practice, Cardiovascular Drugs and Therapy, Cardiovascular Research, Circulation, Clinical Biochemistry, Clinical Chemistry and Laboratory Medicine, Clinical Pharmacology and Therapeutics, Critical Care, Critical Care Medicine, Diabetes Research and Clinical Practice, European Heart Journal, European Journal of Cardiovascular Nursing, European Journal of Clinical Investigation, European Journal of Heart Failure, European Journal of Oncology Nursing, Expert Review Molecular Diagnostics, Free Radical Biology & Medicine, Health and Quality of Life, Heart, Heart Vessels, International Journal of Cardiology, International Journal Diabetes in Developing Countries, ISRN Nursing (International Scholarly Research Network), International Journal of Obesity, Intensive Care Medicine, JACC, JACC-HF, JAMA, Journal of Cardiac Failure, Journal of Clinical Laboratory Analysis, Journal of Cardiovascular Medicine,

Journal of Critical Care, Journal of Internal Medicine, Lancet, Life Sciences, Metabolism, Nursing Research, Nutrition Research, PLoS Medicine, PLoS One, PharmacoEconomics, Pharmacological Research, Postgraduate Medical Journal, Recent Patents in Endocrinology Metabolism Immune Drug Discovery, Redox Report, Resuscitation, Trials, Vascular Health Risk Management

NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP

Comitato Etico della Provincia di Trento Comitato Ordinatore del Corso Master di I° Livello in Ricerca Clinica, Università degli Studi di Milano Comitato Scientifico IRC - Italian Resuscitation Council, Bologna Comitato Scientifico ACOI - Associazione Chirurghi Ospedalieri Italiani, Roma Consiglio di Amministrazione Consorzio MIA (Microscopy and Image Analysis), Monza ERC (European Resuscitation Council), Basic Life Support Working and Wriing Groups Gruppo di Studio SIAARTI - Società Italiana Anestesia Analgesia Rianimazione Terapia Intensiva ILCOR (International Liaison Committee on Resuscitation), Task Force for Cardiopulmonary Resuscitation 2015 International Guidelines Società Italiana Terapia Intensiva SITI

EVENT ORGANIZATION

Seminar - Jeffrey E. Saffitz: Arrhythmogenic cardiomyopathy - New insights into disease mechanisms and drug discovery 21/04/15, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milano Corso di telemedicina -La telemedicina applicata all’elettrocardiografia in medicina generale: corso di formazione sperimentale. 07/05/15, Studio Medico Associato “Comunità Medica”, Milano 18/06/15, Studio Medico Associato “Comunità Medica”, Milano Seminar - Jeff Healey: One year follow-up of patients presenting to the emergency department with atrial fibrillation: 23/06/15, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milano MASTER di I° Livello in Ricerca Clinica dell’Università degli Studi di Milano, Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti (Anno Accademico 2015-2016) METODOLOGIA DELLA RICERCA CLINICA ED ELEMENTI DI STATISTICA 09/11/15 Introduzione al corso. Il disegno dello studio in epidiemiologia. Il disegno degli studi clinici 10/11/15 Elementi di statistica descrittiva. Corso di introduzione alla statistica medica. 11/11/15 Inferenza statistica 1: stima e intervalli di confidenza. Esercitazione di inferenza statistica-1 12/11/15 Metodi statistici per l'analisi dell'outcome. Le principali misure di rischio. L'ORGANIZZAZIONE DI UNO STUDIO CLINICO: ASPETTI REGOLATORI IN ACCORDO CON LE REGOLE DI BUONA PRATICA CLINICA 16/11/15 Good Clinical Practice (GCP). Lo studio clinico: il protocollo, il consenso informato e la

comunicazione con le autorità competenti 17/11/15 Gestione dei dati: gli strumenti. La farmacovigilanza degli studi no profit: nuove direttive e

prospettive future 18/11/15 Gestione della ricerca clinica in Azienda. Gestione della ricerca clinica in un IRCCS 19/11/15 Gestione di qualità del database. Monitoraggio locale negli studi no-profit GLI STRUMENTI PER LA RACCOLTA E L’INTERPRETAZIONE DEI DATI 23/11/15 Farmaci equivalenti. Gestione della complessità clinico-terapeutica del paziente anziano ospedalizzato. Le interazioni tra farmaci 24/11/15 Meta-Analisi. Problemi aperti nella scoperta e nello sviluppo di farmaci 25/11/15 Trasparenza nei clinical trial. Trial di non-inferiorità

26/11/15 La ricerca bibligrafica oggi. Internet e le nuove technologie per l’aggiornamento del medico-scientifico. Il dolore come problema clinico e sociale: il contributo della ricerca

LA RICERCA CLINICA NELLE VARIE AREE TERAPEUTICHE 30/11/15 Il "discorso etico": dalla linearità dei buoni principi alla provocazione del reale. Ricerca clinica nel campo dell'epilessia. Ricerca clinica nell'ictus 02/12/15 Monitoraggio degli studi clinici profit & report delle reazioni avverse. Legislazione sulla

sperimentazione clinica e ruolo dei Comitati Etici 03/12/15 Uso clinico dei biomarker in oncologia. La dimensione del campione negli studi clinici 09/12/15 Reazioni avverse e farmacovigilanza. Dalla preclinica alla clinica: sviluppo di nuovi farmaci

cardiovascolari ELEMENTI DI STATISTICA AVANZATA 10/12/15 Inferenza statistica 2: Test statistici. Analisi della sopravvivenza IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milano

CONFERENCE AND WORKSHOP CONTRIBUTIONS International Liaison Committee on Resuscitation, American Heart Association. ILCOR C2015, International Consensus on CPR & ECC Science with treatmet recommendations, 31/01-05/02/15, Dallas, USA - ALS 470: Defibrillation strategies for VR or VT Fondazione Associazione Medici Diabetologi AMD, Fondazione per il tuo cuore Onlus-Heart Care Foundation. Investigator Meeting DYDA 2 Trial, 19/03/15, NH Bologna De La Gare, Bologna, Italy - Prelievi per il laboratorio centralizzato European Cardiac Arrhythmias Society. ECAS 2015, 11th Annual Congress of the European Cardiac Arrhythmias Society. 19-21/04/15, Parigi, France - Ranolazine ameliorates post-resuscitation electrical instability and myocardial dysfunction and improves

outcome in a rat model of ventricular fibrillation Weil Institute of Critical Care Medicine.Thirteenth Wolf Creek Conference on Cardiopulmonary Resuscitation. 15-18/04/15, Shanghai, China - Early activation of the kynurenine pathway predicts early death and long-term outcome in patients

resuscitated from out-of-hospital cardiac arrest SMART - Organizing and Scientific Committee. 26° SMART - Simposio Mostra Anestesia, Rianimazione e Terapia Intensiva. 27-29/05/15, MiCo-Milano Congressi Ala Nord, Milano, Italy - Cardiac arrest and systemic inflammation - Circulatin cardiac biomarkers in severe sepsis. Albumin Italian Outcome Sepsis (ALBIOS) Study Comunità Medica, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”. Corso di telemedicina. La telemedicina applicata all’elettrocardiografia in medicina generale: corso di formazione sperimentale. 07-05-15, Studio Medico Associato “Comunità Medica”, Milano, Italy - Aritmie in Medicina Generale. L’identificazione dei pazienti con aritmie - Lo screening della fibrillazione atriale ITACTA - Società Italiana di Anestesia e Terapia Intensiva Cardio-Toraco-Vascolare. I° Congresso Nazionale ITACTA. 3-5/06/15, Firenze, Italy - Novità in tema di Advanced Life Support ESHG European Society of Human Genetics, Congress 2015. 05-09/06/15, Glasgow, Scotland (UK) - Influence of genetic variants on heart failure occurrence and outcomes in an Italian population

Comunità Medica, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”. Corso di telemedicina. La telemedicina applicata all’elettrocardiografia in medicina generale: corso di formazione sperimentale. 18-06-15, Studio Medico Associato “Comunità Medica”, Milano, Italy - Aritmie in Medicina Generale. Verifica dei tracciati e problemi emersi Biobanking and Biomolecular Resources Research Infrastructure. HandsOn Biobanks 2015. 29-31/07/2015, Milano, Italy - From cardiovascular and oncological clinical studies to a certified research biobank: a long and winding road Università degli Studi di Palermo. I° Meeting Mediterraneo Anestesiologia Rianimazione Emergenza. 10-12/09/15, Centro Ricerche e Studi Direzionali, Palermo, Italy - Arresto cardiaco “Update 2015” ESS European Shock Society. 16th Annual Congress ESS. 24-29/09/15, Cologne, Germany - SCK-3: Target metabolomics for improving early prediction of death in patients with septic shock SIAARTI Società Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva. 69° Congresso Nazionale SIAARTI. 14-17/10/15, Palazzo della Cultura e dei Congressi, Bologna, Italy - Basic Life Support-D 2015 - CPR: quale tecnica per le compressioni toraciche e per la ventilazione? Boehringer - Ingelheim (I). GLORIA-AF Global Registry on Long-Term Oral Antithombotic Treatment in Patients with Atrial Fibrillation. Investigators’ Meeting, 27/10/15, Boehringer Ingelheim, Milano, Italy - Why do we need observational studies? Università degli studi di Siena. Comorbidities in heart failure: from guidelines to clinical pracitce. 29-30/10/15, Auditorimum “Centro Didattico Le Scotte”, Siena, Italy - Social impact and prevalence of heart failure in industralized countries: clinical characteristics of multi center trials ERC European Resuscitation Council. Resuscitation 2015 - The Guidelines Congress. 29-31/10/15, Prague, Czech Republic - Optimising CRP … Based on physiological response IRC Italian Resuscitation Council. Congresso Nazionale IRC 2015. Le nuove linee guida 2015 della Rianimazione Cardiopolmonare. 06-07/11/15, Centro Congressi Pala Cassa, Parma, Italy - RIAC 2015 & EuReCA Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello di Palermo. Caso …. e la necessità. Lo scompenso cardiaco tra linee guida e linee d’ombra. 13-14/11/15, Villa Malfitano, Palermo, Italy - La ricerca di base American Heart Association. AHA Annual Meeting, Scientific Session, 07-11/11/15, Orlando, Florida, USA - BeTACTIC Study - Best Therapy After Cardiac Transplantation, the Italian Challenge Croce Rossa Italiana. From the strategy to the way. II^ Edizione. Croce Rossa. Persone in prima persona. 27-29/11/15, Bologna, Italy - Ottimizzare la RCP SITI Società Italiana di Terapia Intensiva. 27° Congresso Nazionale della Società Italiana di Terapia Inteiva. 1975-2015 40° Anniversario. 02-05/12/15, Firenze, Italy - BLS & ALS 2015, cosa è cambiato? SIAARTI Società Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva, UMG Università degli Studi Magna Grecia. XI° Meeting di Anestesia e Terapia Intensiva. Le nuove linee guida della rianimazione

cardiopolmonare 2015. 16/12/15, Università degli Studi Magna Grecia, Aula Magna C, Corpo G, Livello 1, Campus Germaneto, Catanzaro, Italy - Le nuove linee guida della rianimazione cardiopolmonare 2015

GRANTS AND CONTRACTS AIFA (Agenzia Italiana del Farmaco), Associazione Amici del Mario Negri, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda Milano, Azienda Ospedaliera Luigi Sacco Milano, Azienda Ospedaliera San Gerardo Monza, Boehringer Ingelheim Italia Spa, Chiesi Farmaceutici SpA, Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, Comunità Europea, DiaSorin SpA, Elior Ristorazione SpA, Fondazione Associazione Medici Diabetologi (AMD) Roma, Fondazione Banca del Monte di Lucca, Fondazione Cassa di Risparmio di Lucca, Fondazione San Raffaele del Monte Tabor Milano, Fondazione per il Tuo Cuore - Heart Care Foundation Onlus Firenze, Fondazione Sestini Bergamo, Grifols SA, Helsinki University - Central Hospital, Istituto Auxologico Italiano IRCCS Milano, Istituto Europeo di Oncologia IRCCS Milano, Laerdal Foundation for Acute Medicine Stavanger, Mayo Clinic, Ministero della Salute, Novartis Pharma SpA, Novo Nordisk SpA, Perfetti Van Melle SpA, Population Health Research Institute-Mc Master University, Regione Lombardia, ROCHE Diagnostics, Sphingotec GmbH, SIAARTI, Università degli Studi di Milano

SCIENTIFIC PUBLICATIONS (2015) Avanzini F, Marzona I, Baviera M, Barlera S, Milani V, Caimi V, Longoni P, Tombesi M, Silletta MG, Tognoni G, Roncaglioni MC, The Risk & Prevention Collaborative Group Improving cardiovascular prevention in general practice: results of a comprehensive personalized strategy in subjects at high risk Eur J Prev Cardiol 2015; Nov 2. pii: 2047487315613664

Abdul-Rahim AH, Perez A-C, Fulton RL, Jhund PS, Latini R, Tognoni G, Wikstrand J, Kjekshus J, Lip GYH, Maggioni AP, Tavazzi L, Lees KR, McMurray JJV, Investigators of the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), GISSI-Heart Failure (GISSI-HF) Committees and Investigators Risk of stroke in chronic heart failure patients without atrial fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials Circulation 2015; 131: 1486-1494

Agresta F, Campanile FC, Vettoretto N, Silecchia G, Bergamini C, Maida P, Lombari P, Narilli P, Marchi D, Carrara A, Esposito MG, Fiume S, Miranda G, Barlera S, Davoli M, Italian Surgical Societies Working Group Laparoscopic cholecystectomy: consensus conference-based guidelines Langenbecks Arch Surg 2015; 400: 429-453 Avanzini F, Mafrici A, Riva E, Franzosi MG, Milani V, Giudici V, Marelli G, Mariani G, Piatti PM, Roncaglioni MC, GLICINE-SPIDER Collaborative Group A multicenter observational study on the management of hyperglycemia in patients with acute coronary syndrome Nutr Metab Cardiovasc Dis 2015; 25: 916-923 Avanzini F, Marelli G, Saltafossi D, Longhi C, Carbone S, Carlino L, Planca E, Vilei V, Roncaglioni MC, Riva E, DDD Study Group Effectiveness, safety and feasibility of an evidence-based insulin infusion protocol targeting moderate glycaemic control in intensive cardiac care units Eur Heart J Acute Cardiovasc Care 2015; Mar 3. pii: 2048872615574110

Barbui T, Masciulli A, Marfisi RM, Tognoni G, Finazzi G, Rambaldi A, Vannucchi A White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study Blood 2015; 126; 560-561

Bouybayoune I, Mantovani S, Del Gallo F, Bertani I, Restelli E, Comerio L, Tapella L, Baracchi F, Fernandez-Borges N, Mangieri M, Bisighini C, Beznoussenko GV, Paladini A, Balducci C, Micotti E, Forloni G, Castilla J, Fiordaliso F, Tagliavini F, Imeri L, Chiesa R Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease

PLoS Pathog 2015; 11: e1004796 CARDIoGRAMplusC4D Consortium A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47: 1121-1130 Cholesterol Treatment Trialists' (CTT) Collaboration Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials Lancet 2015; 385: 1397–1405 Cortese B, Ielasi A, Romagnoli E, Varricchio A, Cuculo A, Loi B, Pisano F, Corrado D, Sesana M, La Vecchia L, Summaria F, Tespili M, Silva Orrego P, Tognoni G, Steffenino G Clinical comparison with short-term follow-up of bioresorbable vascular scaffold versus everolimus-eluting stent in primary percutaneous coronary interventions Am J Cardiol 2015; 116: 705-710 Cortese B, Ielasi A, Varricchio A, Tarantini G, La Vecchia L, Pisano F, Facchin M, Gistri R, D'Urbano M, Lucci V, Loi B, Tumminello G, Colombo A, Limbruno U, Nicolino A, Calzolari D, Tognoni G, Defilippi G, Buccheri D, Tespili M, Corrado D, Steffenino G, BVS-RAI Investigators Registro Absorb Italiano (BVS-RAI): an investigators-owned and -directed, open, prospective registry of consecutive patients treated with the Absorb™ BVS: study design Cardiovasc Revasc Med 2015; 16: 340-343 Cosmi F, Di Giulio P, Masson S, Finzi A, Marfisi RM, Cosmi D, Scarano M, Tognoni G, Maggioni AP, Porcu M, Boni S, Cutrupi G, Tavazzi L, Latini R, GISSI-HF Investigators Regular wine consumption in chronic heart failure: impact on outcomes, quality of life and circulating biomarkers Circ Heart Fail 2015; 8: 428-437 Emdin M, Fatini C, Mirizzi G, Paoletti R, Borrelli C, Pontera C, Latini R, Passino C, Clerico A, Vergaro G Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible? Clin Chim Acta 2015; 443: 85-93 Frånberg M, Gertow K, Hamsten A, PROCARDIS Consortium, Lagergren J, Sennblad B Discovering genetic interactions in large-scale association studies by stage-wise likelihood ratio tests PLoS Genet 2015; 11: e1005502 Fratelli M, Bolis M, Kurosaki M, Dori M, Guarnaccia V, Spinelli O, Alberti M, Valoti Elisabetta, Pileggi S, Noris M, Remuzzi G, Rambaldi A, Terao M, Garattini E Association of CFHR1 homozygous deletion with acute myelogenous leukemia in the European population Leuk Lymphoma. 2015; Aug 28: 1-17 Guzzetti S, Bassani T, Latini R, Masson S, Barlera S, Citerio G, Porta A Autonomic cardiovascular modulation with three different anesthetic strategies during neurosurgical procedures Minerva Anestesiol 2015, 81: 3-11 He M, Gong Y, Li Y, Mauri T, Fumagalli F, Bozzola M, Cesana G, Latini R, Pesenti A, Ristagno G Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests Crit Care 2015; 19: 425 Latini R, Masson S Understanding and making good use of changes in natriuretic peptide levels in chronic heart failure Eur J Heart Fail 2015; 17: 758-759 Li M, Armelloni S, Zennaro C, Wei C, Corbelli A, Ikehata M, Berra S, Giardino L, Mattinzoli D, Watanabe S, Agostoni C, Edefonti A, Reiser J, Messa P, Rastaldi MP BDNF repairs podocyte damage by microRNA-mediated increase of actin polymerization J Pathol 2015; 235: 731-744 Loconsole C, Frisoli A, Mastronicola N, Stroppa F, Ristagno G, Marchetti L, Semeraro F RELIVE Tracking for quality cardiopulmonary resuscitation training: An experimental comparison with a standard CPR training mannequin Resuscitation 2015; 93: e1-e2 Marelli G, Avanzini F, Iacuitti G, Planca E, Frigerio I, Busi G, Carlino L, Cortesi L, Roncaglioni MC, Riva E. Effectiveness of a nurse-managed protocol to prevent hypoglycaemia in hospitalized patients with diabetes J Diabetes Res 2015, Article ID 173956, 8 pages

Masson S, Agabiti N, Vago T, Miceli M, Mayer F, Letizia T, Wienhues-Thelen U, Mureddu GF, Davoli M, Boccanelli A, Latini R, PREDICTOR Study Group The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk J Intern Med 2015; 277: 318-330 Masson S, Caironi P, Fanizza C, Carrer S, Caricato A, Fassini P, Vago T, Romero M, Tognoni G, Gattinoni L, Latini R, ALBIOS Study Investigators Sequential N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin measurements during albumin replacement in patients with severe sepsis or septic shock Crit Care Med, 2015, Nov 13 Epub Masson S, Caironi P, Fanizza C, Thomae R, Bernasconi R, Noto A, Oggioni R, Pasetti GS, Romero M, Tognoni G, Latini R, Gattinoni L, ALBIOS Study Investigators Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial Intensive Care Med 2015; 41: 12-20 Masson S, Wu JHY, Simon C, Barlera S, Marchioli R, Mariani J, Macchia A, Lombardi F, Vago T, Aleksova A, Dreas L, Favaloro RR, Hershson AR, Puskas JD, Dozza L, Silletta MG, Tognoni G, Mozaffarian D, Latini R, OPERA Investigators Circulating cardiac biomarkers and postoperative atrialfibrillation in the OPERA trial. Eur J Clin Invest 2015; 45: 170-178 Merlanti B, De Chiara B, Maggioni AP, Moreo A, Pileggi S, Romeo G, Russo CF, Rizzo S, Martinelli L, Maseri A, VAR Study Group Rationale and design of GISSI OUTLIERS VAR Study in bicuspid aortic valve patients: Prospective longitudinal, multicenter study to investigate correlation between surgical, echo distinctive features, histologic and genetic findings in phenotypically homogeneous outlier cases Int J Cardiol 2015:199: 180-185 Nobili A, Pasina L, Latini R Beta-adrenoceptor antagonists and antianginal drugs. Chapter 18 In: Side Effects of Drugs. Annual 37. Elsevier, Amsterdam 2015; 215-222 Parolo S, Lisa A, Gentilini D, Di Blasio AM, Barlera S, Nicolis EB, Boncoraglio GB, Parati EA, Bione S Characterization of the biological processes shaping the genetic structure of the Italian population BMC Genet 2015; 16: 132 Pellis T, Sanfilippo F, Ristagno G The optimal hemodynamics management of post-cardiac arrest shock Best Pract Res Clin Anaesthesiol 2015; 29: 485-495. Perkins GD , Handley AJ, Koster RW, Castrén M, Smyth MA, Olasveengen T, Monsieurs KG, Raffay V, Gräsner J, Wenzel V, Ristagno G, Soar J, Adult basic life support and automated external defibrillation section Collaborators European Resuscitation Council Guidelines for Resuscitation 2015 Section 2. Adult basic life support and automated external defibrillation Resuscitation 2015; 95: 81-99 Pretto F, Ghilardi C, Moschetta M, Bassi A, Rovida A, Scarlato V, Talamini L, Fiordaliso F, Bisighini C, Damia G, Bani MR, Piccirillo R, Giavazzi R Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle Oncotarget 2015; 6: 3043-3054 Ristagno G, Latini R, Plebani M, Zaninotto M, Vaahersalo J, Masson S, Tiainen M, Kurola J, Gaspari F, Milani V, Pettilä V, Skrifvars MB, FINNRESUSCI Study Group Copeptin levels are associated with organ dysfunction and death in the intensive care unit after out-of-hospital cardiac arrest Crit Care 2015; 19: 132 Ristagno G, Mauri T, Cesana G, Li Y, Finzi A, Fumagalli F, Rossi G, Grieco N, Migliori M, Andreassi A, Latini R, Fornari C, Pesenti A, Azienda Regionale Emergenza Urgenza (AREU) Research Group Amplitude spectrum area to guide defibrillation: A validation on 1617 ventricular fibrillation patients Circulation 2015; 131: 478-487 Ristagno G, Varpula T, Masson S, Greco M, Bottazzi B, Milani V, Aleksova A, Sinagra G, Assandri G, Tiainen M, Vaahersalo J, Kurola J, Barlera S, Montanelli A, Latini R, Pettilä V, Bendel S, Skrifvars M B, FINNRESUSCI Study Group Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death

Clin Chem Lab Med 2015; 53: 1847-1857 Rossignol P, Masson S, Barlera S, Girerd N, Castelnovo A, Zannad F, Clemenza F, Tognoni G, Anand IS, Cohn JN, Anker SD, Tavazzi L, Latini R, GISSI-HF Investigators, Val-HeFT Investigators Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights from GISSI-HF and Val-HeFT Trials Eur J Heart Fail 2015; 17: 424-433 Santalucia P, Baviera M, Cortesi L, Tettamanti M, Marzona I, Nobili A, Riva E, Fortino I, Bortolotti A, Merlino L, Roncaglioni MC Epidemiological trends in hospitalized ischemic stroke from 2002 to 2010: results from a large Italian population-based study J Stroke Cerebrovasc Dis 2015: 24: 1917-1923 Semeraro F, Scapigliati A, Tammaro G, Olcese U, Cerchiari EL, Ristagno G Advanced life support provider course in Italy: A 5-year nationwide study to identify the determinants of course success Resuscitation 2015; 96: 246-251 Staszewsky L, Cortesi L, Baviera M, Tettamanti M, Marzona I, Nobili A, Fortino I, Bortolotti A, Merlino L, Disertori M, Latini R, Roncaglioni MC Diabetes mellitus as risk factor for atrial fibrillation hospitalization: incidence and outcomes over nine years in a region of Northern Italy Diabetes Res Clin Pract 2015; 109: 476-484 Staszewsky L, Masson S, Barlera S, Disertori M, Boni S, Bertoli D, Vriz O, Pasotti E, Zeni P, Vago T, Maggioni AP, Tognoni G, Latini R, GISSI-AF Investigators Cardiac remodeling, circulating biomarkers and clinical events in patients with a history of atrial fibrillation. Data from the GISSI-AF trial Cardiovasc Drugs Ther 2015; 29: 551-561 Tognoni G The challenged but indispensable role of ethical committees for human clinical experimentation Cortex 2015; 71: 420-422 Tortarolo M, Vallarola A, Lidonnici D, Battaglia E, Gensano F, Spaltro G, Fiordaliso F, Corbelli A, Garetto S, Martini E, Pasetto L, Kallikourdis M, Bonetto V, Bendotti C Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression J Neurochem 2015; 135: 109-124 Toscani F, Van der Steen JT, Finetti S, Giunco F, Pettenati F, Villani D, Monti M, Gentile S, Charrier L, Di Giulio P, End of Life Observatory-Prospective Study on DEmentia Patients Care (EoLO-PSODEC) Research Group Critical decisions for older people with advanced dementia: a prospective study in long-term institutions and district home care J Am Med Dir Assoc 2015; 16: 535.e13-535.e20 Wu JHY, Marchioli R, Silletta MG, Masson S, Sellke FW, Libby P, Milne GL, Brown NJ, Lombardi F, Damiano, Jr RJ, Marsala J, Rinaldi M, Domenech A, Simon C, Tavazzi L, Mozaffarian D Oxidative Stress Biomarkers and Incidence of Postoperative Atrial Fibrillation in the Omega-3 Fatty Acids for Prevention of Postoperative Atrial Fibrillation (OPERA) Trial J Am Heart Assoc. 2015; 4: e001886 Zambelli V, Bellani G, Amigoni M, Grassi A, Scanziani M, Farina F, Latini R, Pesenti A The effects of exogenous surfactant treatment in a murine model of two-hit lung injury Anesth Analg 2015; 120: 381-388 Zambelli V, Bellani G, Borsa R, Pozzi F, Grassi A, Scanziani M, Castiglioni V, Masson S, Decio A, Laffey J G, Latini R, Pesenti A Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome Intensive Care Med Exp 2015; 3: 8

LAY PRESS SELECTION (2015)

Latini R, Staszewsky, Ottani F Il ruolo dei mitocondri sul danno da riperfusione coronarica come potenziale target farmacologico: luci ed ombre G Ital Cardiol 2015; 16: 544-548 Di Giulio P Per un aggiornamento che parte dalla pratica

Informazioni sui Farmaci 2015; 39: 26-27 Di Giulio P, Castaldo A, Zanetti E Pro memoria: per quando i contesti pesano più dei problemi Informazioni sui Farmaci 2015; 39: 53-56 Di Giulio P, Castaldo A, Zanetti E I problemi con le terapie in RSA Informazioni sui Farmaci 2015; 39: 86-88 Tognoni G Novità 2015 Informazioni sui Farmaci 2015; 39: 1-2 Tognoni G Evidenze 2015 Informazioni sui Farmaci 2015; 39: 33-35 Tognoni G Rivoluzioni cardiovascolari: ma non solo Informazioni sui Farmaci 2015; 39: 61-62

RESEARCH ACTIVITIES Laboratory of Cardiovascular Clinical Pharmacology Pilot study on microangiopathy in diabetic foot ulcer Microangiopathy is considered one of the major complications in the diabetic foot, although the role of microvascular alterations in the etiopathogenesis and severity of the ulcer in diabetic foot are still unknown. The purpose of this study will be the assessment of microangiopathy determined by the increase of capillary basement membrane thickness and decrease of capillary lumen area by transmission electron microscopy in the foot ulcer of neuropathic and neuroischemic type 2 diabetic patients compared to healthy subjects. Furthermore, we will investigate the correlation between the presence of capillary and thrombosis with ischemic parameters (TcPO2, ankle-brachial index) and between the presence of inflammatory infiltrate with blood inflammatory parameters. Nowadays all the neuroischemic and neuropathic patients have been enrolled in the study and the histopathological analysis are in progress. Albumin Italian Outcome Sepsis Study. The ALBIOS Study (AIFA) ALBIOS is a multicenter, controlled, randomized clinical trial that compares the efficacy of human albumin and a crystalloid solution for volume replacement in patients with severe sepsis or septic shock. The primary endpoint is survival at 28 and 90 days after enrolment. Secondary endpoints include the number of organ dysfunctions, severity of organ dysfunction (SOFA scale), and lengths of stay in intensive care unit (ICU) and in hospital. More than 150 ICU in Italy have enrolled patients in this large study, coordinated by the Ospedale Maggiore Policlinico in Milan and the Consorzio Mario Negri Sud. A group of 50 ICUs participates to a biomarkers substudy, coordinated by the laboratory of Clinical Cardiovascular Pharmacology, and have collected serial blood samples from 1000 patients to measure biomarkers related to inflammation, infection, cardiac function and coagulation. A new marker of sepsis, sCD14-ST or presepsin, has been shown to be strongly associated with the host response and prognosis. Its changes over time are also related to the appropriateness of antibiotic therapy. There is a large ongoing programme of evaluation of markers related to innate immunity (PTX3, in collaboration with the Istituto Clinico Humanitas at Rozzano), cardiac function (Masson et al, Critical Care Medicine, in press), coagulation and fibrinolysis (in collaboration with the University of Bari), immunoglobulins (in collaboration with the University of Brussels), neuropeptides (in collaboration with the University of Oslo), vasoactive peptides (in collaboration with SphingoTec GmbH, Berlin, Germany), and redox function of albumin (in collaboration with Grifols SA, Barcelona, Spain). Within the frame of the EU FP7 ShockOmics project, metabolomic and proteomic makers of septic shock are evaluated (Ferrario et al, Scientific Reports, in press).

Coronary Atherosclerosis in Outlier Subjects: Protective and Individual Risk Factor Evaluation. The GISSI-Outliers CAPIRE study The risk of developing clinical signs of ischemic cardiopathy is currently estimated with multivariable prediction models based on non-modifiable factors like age, sex and family history for early ischemic cardiopathy, and on conventional modifiable risk factors like hypertension, hypercholesterolemia, smoking and diabetes mellitus. However, there is a component of individual variability underlying the fact that a relevant number of individuals with multiple risk factors do not progress to coronary atherosclerosis or have clinical events, while others have such events or coronary disease in the absence of risk factors (= outliers). The purpose of the CAPIRE study is to identify possible novel protective or risk factors for coronary disease in outlier subjects and generate new etiological hypotheses and therapeutic targets for this disease. This is an observational, multicenter clinical study performed in 8 centers. Enrolment of the patients will last 2 years and each patient will be followed for 5 years with yearly clinical visit and phone contact every 6 months. The Laboratory of Clinical Cardiovascular Pharmacology is acting as a core laboratory for the evaluation of circulating biomarkers related to lipid profile, inflammation, metabolism and coagulation. A total of 544 patients have been enrolled, with 5-year follow-up ongoing. A paper on study objectives and design has been published (Magnoni et al., American Heart Journal, in press) while another on the prognostic value of cardiac troponin has been accepted by the American Journal of Cardiology. A circulating marker related to adhesion molecules (CD31 or PECAM-1) is currently being evaluated in collaboration with an INSERM unit in Paris (Dr. Giuseppina Caligiuri) Cyclosporin A in reperfused acute myocardial infarction - The CYCLE study The final extent of myocardial infarction is the main determinant of prognosis in these patients. A preliminary study has shown that a single bolus of cyclosporin A (CsA), administered immediately before primary angioplasty, can reduce the final area of necrosis after a ST-segment elevation myocardial infarction (STEMI). The primary objective of this trial was to assess whether CsA can improve the outcome of a successfully reperfused STEMI, by favoring myocardial reperfusion. Male and female patients, older than 18 years, with a large STEMI will be enrolled within the first 6 hours from symptoms onset and with indication for primary angioplasty (PCI). The secondary objectives were a reduction of high sensitivity cardiac troponin T release 4 days after PCI, total heart failure mortality, cardiogenic shock or hospital admission for cardiovascular reasons within 6 months after randomization. The study has been concluded on date 30th October 2014. A total of 473 patients from 31 sites entered into the study. Its results were published on the web at the end of January 2016 by the Journal of American College of Cardiology showing a neutral effect of CsA on myocardial reperfusion, plasma levels of cardiac troponin and 6 month clinical events and left ventricular remodeling. The study was conducted in collaboration with the Centro Studi ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri). Prevention of anthracycline-induced cardiac toxicity: a multicenter randomized clinical study comparing two strategies - The ICOS-ONE study Chemotherapy with anthracycline often induces a progressive and dose-dependent cardiac injury, reducing left ventricular output. The development of cardiac dysfunction, even if asymptomatic, may have a negative impact on the prognosis of a cancer patient. Measuring circulating cardiac troponin levels during chemotherapy with anthracycline allow to identify early cardiac injury, before the development of overt left ventricular dysfunction. Treatment with ACE inhibitors (ACEi) and beta-blockers (BB) before the elevation of circulating cardiac troponin levels during or after chemotherapy with anthracycline can protect the heart, as shown in a single-center study. Early prophylaxis with enalapril (ACEi) and possibly bisoprolol (BB) may further decrease the incidence of cardiovascular injury and thereby raising the probability of completing the chemotherapy. The primary objective of the ICOS-ONE study is to assess whether a treatment with enalapril given since the beginning of anthracyclin therapy is more efficient in preventing cardiac toxicity compared to the same treatment initiated at the first occurrence of raised troponin levels. Patients with an indication for treatment with anthracyclin for blood and solid cancer are being enrolledin this randomized multicenter clinical trial. In one arm, enalapril was given at the beginning of chemotherapy (primary prevention) while it was indicated only after the troponin elevation in the second arm (secondary prevention). Concomitant therapy with bisoprolol was recommended in both study groups in presence of different clinical or laboratory patterns.The patients are followed for 1 year from the end of chemotherapy with periodical clinical visits and once a year for other two years.

Patients randomization was completed on May 15th 2015 and a total of 273 patients have been enrolled in 21 centers. This trial is promoted by the IEO (Istituto Europeo di Oncologia) and coordinated in collaboration with the Laboratory of Clinical Drug Evaluation. Biological markers in patients with traumatic brain injury. A European collaborative project in Intensive Care Units. CREACTIVE - Collaborative REsearch on ACute Traumatic brain Injury in intensiVe care medicine in Europe Traumatic brain injury (TBI) is one of the main causes of death and disability in Western countries and the main cause of death for individuals below age 45 years. Most of the patients with mild-severe grades of TBI are admitted in Intensive care Units. PROSAFE is a recent collaborative network PROSAFE of ICUs in six European countries, under the coordination of the Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (GiViTi). The clinical study CREACTIVE, funded by a grant from the European Union (FP7–HEALTH–2013-INNOVATION-1), is a part of this collaborative network, with the following objectives: to better describe the epidemiology of mild-to-severe traumatic brain injury in 7 countries (Cyprus, Greece, Israel, Italy, Poland, Slovenia, Hungary); to collect and store in central repositories biological samples and clinical images, to evaluate their prognostic value; to build a prognostic model based on clinical and biological variables to predict short-term and long-term outcomes of TBI patients; to identify more effective therapeutic interventions in TBI; to identify centers of excellence in the treatment of mild-severe TBI. In a subgroup of ICUs, biological samples (blood and cerebrospinal fluid) from approximately 2000 patients will be collected and stored in a central repository. The laboratory of Cardiovascular Clinical Pharmacology will act as a core laboratory for the collection of biological samples and the assay of phenotypic markers associated with brain damage, inflammation, hypothalamic pituitary axis, and coagulation disorders. The protocols for biological samples collection are ready. The materials for sample collection has been distributed to the clinical centers during the kick-off meeting of the subproject. By the end of 2015, biological samples from 353 patients in Italy have been collected in clinical centers and stored in the biobank. More countires will be recruited in 2016. Heart “Omics” in AGEing - HOMAGE The concept of HOMAGE, a collaborative project financed by a European Union grant under the FP7 Health 2012.2.1.1-2 program, is that, in older people, “omics” based biomarkers can detect asymptomatic pathological processes that predict who will develop of heart failure and other common serious cardiovascular conditions and characterize distinct phenotype(s) more likely to respond to targeted preventive therapy that could efficiently promote active healthy ageing. The objectives of the HOMAGE project are (i) to identify “omics” based biomarkers that reflect specific pathological pathways (early diagnosis) leading to HF and other serious cardiovascular conditions that are also potential targets for therapy (stratification for personalized medicine), (ii) to validate the predictive value of these biomarkers for the development of HF and commonly associated co-morbid conditions, and (iii) to demonstrate the feasibility of an “omics” biomarkers -based approach to select patients for whom treatment will prevent or delay the onset of HF. The laboratory of Clinical Cardiovascular Pharmacology is contributing to the HOMAGE consortium by sharing selected biological samples and related clinical data from patients with type II diabetes (in collaboration with the ANMCO Research Center and the Italian Association of Clinical Diabetologists) and from elderly individuals (in collaboration with the Department of Epidemiology and cardiologist of the Lazio Region). The aims and methods used for this project have been published (Jacobs et al, J Biomed Res J Biomed Res 2014; 28: 349-359). The laboratory is also involved in a proof-of-concept clinical study that will evaluate the efficacy of heart failure therapy based on the knowledge of omics-derived biomarkers. The first samples e clinical data from a cohort of elderly subjects have been made available to the HOMAGE consortium. The protocol and operative procedures of the clinical study have been approved by local regulatory authorities. The enrolment of the first patient is scheduled for Q1 2016. Effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on left ventricular dysfunction in patients with type 2 diabetes mellitus and concentric geometry of the left ventricle - DYDA2 The aim of this multicentric study is to evaluate the effect of adding linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4) on left ventricular function in well-controlled patients with type 2 diabetes mellitus on usual therapy. The randomized, placebo-controlled clinical trial will enroll patients with LV concentric

geometry, as defined by previous echocardiography. The efficacy and safety of linagliptin as an add-on therapy will be assessed in diabetic patients with asymptomatic LV systolic dysfunction. The trial is coordinated by the National Association of Diabetologists (AMD) and the National Association of Hosital Cardiologists (ANMCO). Our laboratory will serve as a central biobank for the evaluation of plasma and urine biomarkers. By the end of 2015, 43 out the 186 patients expected have been enrolled.

Laboratory of Cardiopulmonary Pathophysiology Preclinical and clinical studies in cardiac arrest and cardiopulmonary resuscitation 700,000 Europeans sustaining cardiac arrest each year. Instead of the initial success of cardiopulmonary resuscitation, the majority victims die within 72 hours because of severe heart contractile failure due to postresuscitation myocardial dysfunction. Furthermore, cardiac arrest and cardiopulmonary resuscitation represent a condition of systemic ischemia reperfusion injury causing multi-organ damage. For this purpose we are currently studying a preclinical model of cardiac arrest and cardiopulmonary resuscitation (CPR) in rats and in pigs (in collaboration with University of Milan) aiming to: (a) evaluate inflammatory response and organ dysfunction after return of spontaneous circulation; (b) evaluate success of cardiopulmonary resuscitation manoeuvres and survival after new interventional approaches. Experimental studies in the pig directed to investigate new treatments to improve outcome of acute heart failure are also ongoing in our labs. Effects of ranolazine on myocardial dysfunction and neurological recovery after cardiac arrest in the rat Several experimental and pathological conditions can specifically increase the late component of the sodium channel current, including hypoxia, heart failure and myocardial infarction. Indeed, deregulation of intracellular calcium (Ca2+) homeostasis plays a critical role in the pathophysiology of ischemia/reperfusion injury occurring after cardiac arrest and cardiopulmonary resuscitation (CPR), leading to electrical instability, heart contractile failure and mitochondrial dysfunction. Preclinical data have demonstrated a consistent attenuation of ischemia/reperfusion myocardial injury when the Na+-dependent rise in intracellular Ca2+ concentration was limited by Na+ channels blockade. Thus, ranolazine, a INaL blocker might reduce post resuscitation intracellular Ca2+ overload, leading to lesser post resuscitation arrhythmia and improved survival and recovery in a well established and clinically relevant rat model of cardiopulmonary resuscitation after cardiac arrest induced by ventricular fibrillation. The study is supported by the Laerdal Foundation for Acute Care, Norway. Role of kynurenine in outcome of cardiac arrest The pathophysiological state recently named “post-cardiac arrest syndrome” (PCAS) is characterised by myocardial dysfunction with circulatory shock, systemic inflammation with activation of the clotting system, and evolving brain injury. Accordingly, there are evident similarities between sepsis, septic shock and PCAS. Indeed, upon reperfusion following cardiac arrest a possible sequence of events includes a systemic inflammatory response that contributes to worsening of circulatory shock and neurological injury. Recently, the activation of the enzyme indoleamine 2,3-dioxygenase (IDO), responsible for the metabolism of the essential amino acid tryptophan (TRP) to kynurenine (KYN), the first step of the so called “kynurenine pathway” (KP), has been highlighted in septic shock patients. The activation of this pathway results in increased levels of KYN which in turn causes vasodilatation. Interestingly, the KP activation has also been implicated in instances accounting for neurological injury, i.e. stroke and cerebral dysfunction in intensive care unit (ICU) patients, as well as in adverse prognosis in patients with coronary artery disease. We have previously demonstrated that KP is activated early following cardiac arrest and correlates with neurological injury and survival both in animals and humans. New studies are now under progress aiming to inhibit the enzyme initiating the TRP catabolism into KYN, the IDO)enzyme. IDO inhibition could prevent KP activation and improve neurological recovery. The study is supported by the “Amici del Mario Negri” Association. Preclinical studies on treatment with inhaled argon and neurological outcome and survival after cardiac arrest

Morbidity and mortality after successful CPR largely depend on recovery of neurologic function. In some instances, only 2-12% of resuscitated patients have been discharged from hospital without neurological dysfunction. Novel therapeutic approaches have been conceived in the last decade, including noble gases, to allow for cerebral and myocardial preservation. Although noble gases are known as "inert" gases, they are capable to interact with aminoacids in the active sites of enzymes or receptors, producing biological effects. Argon has shown neuroprotective and cardioprotective properties in both "in vitro" and "in vivo" studies in different ischemia models. Argon, in contrast to other noble gases, is abundant and inexpensive, and therefore widely applicable. The project optimizes, in terms of dose, timing and duration of treatment, a new therapeutic approach by inhalation of the noble gase argon, for brain and heart protection after myocardial infarction (MI) and cardiac arrest. Experiments are performed in a preclinical porcine model of myocardial infarction, cardiac arrest and cardiopulmonary resuscitation (CPR). This model has been successfully employed over the last decades, demonstrating clinical relevance in terms of pathophysiology of ischemic injury, development of myocardial and neurological dysfunction, and response to drugs/interventions. An optimized protocol of treatment with inhaled argon, to be later translated into clinical practice, will be identified in these preclinical studies. Finally, the association of inhaled argon with therapeutic hypothermia will lead to a boosted neurological protection after cardiac arrest. Preliminary results were obtanied in animals subjected to 8 mins of untreated cardiac arrest and 5 mins of CPR. After return of spontaneous circulation (ROSC), animals were divided to: a. 4 hrs ventilation with a mixture of 70% argon-30% oxygen; or b. 4 hrs of control ventilation with a mixture of 70% nitrogen-30% oxygen. 12/14 pigs were successfully resuscitated. 6/6 animals survived for 72 hrs in the argon group, and 5/6 in the control group. Animals that received argon showed a trend toward a better post resuscitation arterial pressure and left ventricle ejection fraction recovery. Ventilation with argon did not impair both respiratory exchange and arterial blood gases. More importantly, animals ventilated with argon achieved a fast and complete neurological recovery, already 24 hrs after ROSC, in contrast to those ventilated with nitrogen and oxygen (p<0.01), in which a neurological impairment persisted up to 72 hours after resuscitation. Histopathology showed lesser brain injury in animals that were treated with argon compared to control ones. In addition, a trend towards a smaller myocardial left ventricle infarct size was observed after inhalation of argon. This histological finding was confirmed by a three fold lower post resuscitation increase in plasmatic troponin T in pigs that received argon in comparison to those subjected to control ventilation. The study is supported by the Italian Ministry of Health “Bando Giovani Ricercatori” and by Fondazione Sestini, Bergamo. Effects of treatment with serelaxin, recombinant human relaxin-2, after acute heart failure in a preclinical porcine model Acute heart failure (AHF) is characterized by a gradual or rapid onset of new or worsening signs and/or symptoms of heart failure requiring urgent therapy, usually resulting in hospitalization. Indeed, AHF is the most common cause for hospital admission in patients > 65 years, with approximately 1 million hospitalizations annually in the United States and Europe. Despite improvements in the management of chronic HF, the prognosis after hospitalization for AHF remains bleak, with rates of death or recurrent hospitalization at 6 months approaching 50%. The Pre-RELAX-AHF Phase II trial was designed to assess serelaxin, recombinant human relaxin-2, effects on multiple end points, including symptoms, signs, and short-term outcomes in patients with AHF. A total of 234 patients hospitalized with dyspnea due to AHF were randomly assigned to receive placebo or one of four active doses of relaxin (10, 30, 100, or 250 μg/kg/d) for 48 h. A clear vasodilatory effect of relaxin was seen in the greater reduction of blood pressure in relaxin-treated patients compared with those receiving placebo, despite greater use of diuretics and intravenous nitroglycerin in the placebo group. Patients treated with relaxin also demonstrated trends toward greater resolution of congestion, improved morbidity and mortality. The dose in Pre-RELAX-AHF that was associated with the greatest benefit was 30 μg/kg/d. That dose was further tested in the RELAX-AHF phase III trial. The study, enrolling 1.161 patients admitted to hospital for AHF, confirmed the beneficial effects of serelaxin on dyspnea relief and other clinical outcomes of AHF. Thus, evidence indicates beneficial actions of serelaxin in cardiovascular pathology. Experimental research, mainly including models of ischemia/reperfusion or myocardial infarction, has documented multiple cardioprotective actions of relaxin against key disease components, including myocardial injury, vasoconstriction, oxidative stress, fibrosis and inflammation. Nevertheless, there is a lack of experimental studies on preclinical models of AHF with pulmonary congestion. Accordingly, testing the effects of serelaxin in a model of AHF in the pig is expected to help to better understand the role of serelaxin on the pathophysiology of AHF. This project aims: to investigate in a preclinical model in the pig (a) possible mechanisms responsible for the beneficial effects of

serelaxin in AHF, (b) safety of serelaxin when started at systolic blood pressures lower than 125 mmHg, thus broadening its indications. Finally, safety of a second treatment with serelaxin is assessed. A preclinical study on association of betablockers and adrenaline during cardiopulmonary resuscitation in a pig model The present study has the aim to investigate the effects of a different vasopressor approach during cardiopulmonary resuscitation, namely administration of the short acting beta1 adrenergic blocker agent, esmolol hydrochloride, together with epinephrine, on outcome of cardiac arrest. This experimental study would be a valid pre-clinical investigation such to validate the proposed treatment prior to translation into a future clinical pilot study. Administration of the short acting beta1 adrenergic blocker, esmolol hydrochloride, in combination with epinephrine, during cardiopulmonary resuscitation would reduce myocardial ischemic injury and would reduce post resuscitation myocardial dysfunction, and would ultimately improve outcome of cardiac arrest, in comparison with animals treated with epinephrine alone. The study is supported by the Società Italiana di Anestesia, Rianimazione e Terapia Intensiva (SIAARTI) Studies on defibrillation The early use of a defibrillator is, along with chest compressions, the only intervention able to restore spontaneous circulation and to improve survival in victims of cardiac arrest caused by ventricular fibrillation. However, timing of defibrillation in relationship to chest compression is a subject of major interest because it is difficult to determine the priority of intervention once rescuer arrives at the cardiac arrest scene, namely chest compression or defibrillation first. Indeed, there are no parameters available that allow the rescuer to determine whether it is more effective to perform chest compression or electrical defibrillation as initial treatment. The real-time analysis of the electric waveform of ventricular fibrillation seems to be an useful and non-invasive way to set a strategy for successful resuscitation. In particular, the algorithm that enables the spectral analysis of the ventricular fibrillation waveform, generates a value, called AMSA, that represents one of the most accurate predictor of the success of defibrillation. At present, we are evaluating a clinically applicable method based on electrocardiographic analysis of ventricular fibrillation waveform aiming to asses a non-invasive approach in order to guide the priority of interventions, namely chest compression or defibrillation (collaborating institutions: Emergency Department, San Gerardo Hospital, Monza and Azienda Regionale Emergenza Urgenza - Lombardia). Based of the encouraging results, a prospective interventional study is under planning. Studies on pulmonary arterial hypertension Primary pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevation of pulmonary artery pressure, increased vascular resistances and eventually right-sided heart failure. This clinical condition is induced by vascular remodeling of the small pulmonary arterioles, consisting of vasoconstriction and medial hypertrophy. The current pharmacological treatment of patients with primary PAH includes prostanoids, endothelin receptor antagonists (i.e. bosentan), phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulants or, rarely, calcium channel blockers. Importantly, these treatments improve symptoms but do not prevent the untimely death due to the right heart failure. These considerations emphasize the urgent need to identify more effective therapies. The monocrotaline (MCT) rat model represents the most frequently investigated model of PAH because of its reproducibility. Current studies, in collaboration with Chiesi Farmaceutici, Parma, Italy, aim to describe the pathophysiology of the MCT model of PAH: modifications of pulmonary arterial pressure and right ventricular function over time; modifications in the circulating biomarkers of myocardial injury, i.e. troponins and natriuretic peptides; discovering of new and more efficient drug treatments. Multiscale approach to the identification of molecular biomarkers in acute heart failure induced by shock - ShockOmics This project, funded by the European Union (FP7), coordinated by Giuseppe Baselli, Politecnico di Milano (Electronic, Information and Bioengineering Department, Bioengineering Section), aims at investigating physiopathologic mechanisms in different types of shock. The Mario Negri Unit, led by Giuseppe Ristagno, will set up and study the consequences of hemorragic shock on myocardial function in the pig, by multiple approaches, hemodynamics, echocardiography, circulating biomarkers, histology, immunohistochemistry.

Within the same project, new circulating biomarkers in humans will be searched for by metabolomic techniques.

Laboratory of General Practice Research Risk and Prevention Study (R&P) R & P, a study on the optimization of cardiovascular prevention in high-risk patients conducted at national level by general practitioners (GPs), had two main objectives: one epidemiological and one experimental. The goal of the epidemiological study was to evaluate the effectiveness of a personalized approach for the implementation of preventive strategies, while the experimental hypothesis was to assess, through a randomized double-blind controlled clinical trial, the efficacy of a daily treatment with n-3 PUFA in reducing the incidence of cardiovascular events, fatal or nonfatal, in a population at high risk. All patients were followed for a mean of five years. Update of the study The study was completed in 2011 and 12 521 patients were randomised by a network of 860 GPs. Data of the epidemiological part of the study confirm that a personalized approach, through the use of a checklist for the assessment of the single patient risk profile and the shared decision on treatment priorities, increase the adherence to the preventive treatments and is associated to a reduction of major cardiovascular events (non fatal myocardial infarction, non fatal stroke and cardiovascular mortality). Other analyses on the risk profile of specific category of patients (with diabetes, hypertension, hyperlipidemia) are ongoing. FARMAGOOD Project Farmagood is a collaborative project in which the IRCCS - Institute for Pharmacological Research Mario Negri (IRFMN) makes available to the Regional Health Service its scientific expertise in the field of pharmacology with the aim of: - Plan activities aimed at integrating components of innovation and training to address critical issues in

regional prescriptive; - Develop new methods to involve health professionals, patients and citizens in programs of rationalization

of the use of drugs in at-risk populations and in specific areas of care and treatment; - Initiate independent comparative clinical studies, systematic reviews and meta-analysis to answer specific

questions of public health priority. The first phase of this project was addressed to the issue of the appropriateness of use of biological medicinal products covered by a patent ("originators") and non - patent biologics ("biosimilars") with the implementation of the Project FARMAGOOD - biosimilars. The second phase of the project involves the conduction of studies aimed to improve the appropriateness and rationalization of resources in other areas of regional interest and independent randomized controlled trials with the aim of producing clinical evidence documenting, through appropriate methodologies, that lower cost treatments with the same efficacy and safety of more expensive ones, can be implemented in the clinical practice. The project is run in cooperation with the Laboratory for Assessment of Quality of Care and Services for the Elderly and the Centre for Health Economics A. and A. Valenti (CESAV). The health care and economic burden of subjects at high cardiovascular risks in the Lombardy Region The study is part of a collaboration between the IRCCS-IRFMN and the Lombardy Region (Agreement EPIFARM 2013-2016) which has the overall objective to implement models for the evaluation and control of health care resources in subjects at high cardiovascular risk, through the use of administrative databases. These databases include data of the resident population (encrypted) of the region of Lombardy (2000-2012) relating to: demographic data, drug prescriptions, laboratory test and medical exams and hospital discharges. The objective of the work is to link the information of these databases to identify the pathways of management of subjects at high cardiovascular risk comparing with the recommendations and evidence, in order to promote the appropriate use of health care and economic resources. In the year 2015 the following analyses were performed:

- The association between the Atrial Fibrillation (AF) and incidence of dementia in elderly population

(> 65 years old) in the Lombardy region from 2003 to 2012 We identified subjects with a diagnosis of AF during a hospital admission in 2002 year and followed-up for ten years to evaluate the incidence of hospital admission for dementia. Patients with AF were compared with the population without AF. Our data show that AF is associated with a significantly higher risk of developing dementia in the following years also after adjusting for all confounding variables.

- Outcomes and recommended in patients with Heart Failure (HF) with or without Chronic Obstructive

Pulmonary Disease (COPD) We evaluated the impact of COPD in patients with HF: a) on clinical outcomes mortality and re-hospitalization for HF; b) the changes in drug prescriptions; c) the relationship between recommended therapies and clinical outcomes. We identified two cohorts of patients in 2002 and 2009 respectively (HF noCOPD e HF yesCOPD) and followed-up for four years. Our data show that the risk of developing clinical outcome remains significantly higher in patients with both diseases (HF ayesCOPD) in comparison with other group (HF noCOPD), from 2002 to 2009 besides the optimization of recommended therapies. Use of beta-blockers was associated with a significantly lower risk of all cause-death in both cohorts.

- Comparison of carotid endarterectomy (CEA) and stenting (CAS) in patients with carotid stenosis

We identified patients aged 65 years or older undergoing to CEA or CAS procedures, from 2003 to 2009. We evaluated the safety and efficacy of both procedures at short (30 days) and long-term (4 years) in the real world in terms of all cause-death, hospital admission for stroke or myocardial infarction. Our data show hat the overall rate of peri-procedural events was low and similar between CEA and CAS, while long-term outcome favors CEA respect to CAS. Both treatments seem to be safe in real world when selection of patients meets the recommendation criteria.

“GLICINE-SPIDER” Study “Glicine-Spider” is an observational study carried out in the Coronary Care Units (CCU) of Lombardy. The protocol is a collaboration between the ANMCO (Italian Association of Hospital Cardiologists) Lombardia, AMD (Association of Medical Diabetologists) Lombardia and the Mario Negri Institute. The study is coordinated by the General Practice Research Laboratory and the Clinical Drug Evaluation Laboratory. Hyperglycemia at the onset of an acute coronary syndrome (ACS) constitutes a negative prognostic factor in diabetic and non-diabetic patients and a poor control of blood glucose in the early hours after hospital admission for ACS is an additional unfavourable prognostic factor. Recent guidelines, although recognizing the importance of controlling blood glucose in ACS, do not clearly define therapeutic strategies to apply and glycemic target values of the patients with and without diabetes hospitalized in CCU for a confirmed ACS. The aim of the study is to describe in a large sample of patients hospitalized in CCU for a ACS: the prevalence of diabetes and hyperglycemia the type of treatment and blood glucose control during the acute phase the incidence of mortality and cardiovascular complications occurred during the hospitalization

according to diagnosis and blood glucose level 1282 patients have been included into the study from 31 CCUs. The results show that hyperglicaemia is frequent in patients with ACS and if persisting in the first 24 hours from the event, it is independently associated with a poor prognosis. SECURE study (Secondary prEvention of CardiovascUlaR disease in the Elderly trial) The SECURE study is funded by the European Commission through the Horizon 2020 - PHC-17-2014 - Call titled "Comparing the effectiveness of existing health care interventions in the elderly". In the aging population, the complexity of the treatments and the access to health care, may compromise the adherence to treatments, increasing the number of clinical events. In particular, in cardiovascular prevention, the polypill strategy (with the aim of simplify adherence and improve the control of risk factors), may reduce the risk of death and hospitalizations.

Results of FOCUS study ((Fixed Dose Combination Drug for Secondary Cardiovascular Prevention) (J Am Coll Cardiol 2014; 64: 2071-2082) carried out in Italy (coordinated by IRFMN for Italian centers), Spain and South America, confirms that the polypill improves the adherence compared to drugs administered separately. After the FOCUS study, in which adherence was the primary end point, the SECURE study will assess the efficacy of the polypill on clinical endpoints. The study will be conducted by a consortium of European partners (Spain, Italy, France, Germany, Czech Republic, Poland and Hungary) coordinated by the Centre de Investigationes Cardiovascular (CNIC) in Madrid. The main objective of the SECURE study is to evaluate, through a randomized multicenter open trial, the efficacy of a polypill containing aspirin (100 mg), atorvastatin (20 or 40 mg), ramipril (2.5; 5.0 o 10mg) compared with usual care on the prevention of cardiovascular events (cardiovascular death, hospitalization for myocardial infarction, stroke and revascularization procedures), in an elderly population (aged ≥ 65 years) hospitalized for myocardial infarction. Secondary objectives of the study are: adherence to treatment, lipid profile and blood pressure profiles, safety / tolerability and cost of the polypill pharmacological strategy. The study will involve departments of cardiology which will include 3200 patients in 2 years (600 in Italy). The follow-up study will be 24 months. In Italy have been involved 20 centers of cardiology in which 40 patients will be randomized. The beginning of randomization is estimated for April 2016. “Il Sale è meglio averlo in Zucca” project The project originates from the awareness that Italian diet is excessively rich in salt, and this can cause major cardiovascular diseases. Data available from previous studies showed that a partial reduction in dietary salt intake leads to a decreased incidence and a better control of hypertension. Reduction in dietary salt can, however, compromise food’s taste and therefore this could represent an unacceptable option for the population. It is possible to reduce salt supplement during food preparation without its taste by substituting some foods with other adding up spices and aromatic plants or utilizing salt substitutes. The second phase of the project, conducted in collaboration with the Laboratory of Toxicology and Nutrition Institute Mario Negri and Elior (a leader company of collective catering), had the practical aim to collect data on simple actions to reduce salt content in diet without jeopardize its palatability in order to produce a manual for the cooks of Elior. Based on the experience gained during the first phase of the pilot project and after some meetings in a sample kitchen, guidelines for cooking food with less salt and a "low-sodium" cookbook were finalized. These documents are now available for the cooks employed in Elior and at the moment an evaluation of the adoption of the low sodium guidelines and recepies is ongoing. Studio FALCO: Surveillance of patients with atrial fibrillation in Lombardy treated with oral anticoagulant drugs The new direct oral anticoagulant drugs (DOAC) direct thrombin inhibitors and inhibitors of the activated X factor, are now available on the Italian market for the treatment of the thromboembolic complications in patients with Atrial Fibrillation (AF). Characteristics of these new drugs are, with respect to so far recommended anticoagulant therapy warfarin and acenocumarol (AC), the rapidity of action, the low potential of interactions with other drugs or foods and a stable anticoagulant effect with no need of monitoring INR frequently. These drugs are dabigatran, rivaroxaban and apixaban (which will enter the Italian market soon). It is foorseenable that these characteristics will lead to a rapid transition of the warfarin prescriptions to DOAC prescriptions. This switching will bring a change in the patients’ management (no need of INR monitoring) whom will still need to be monitored for adverse events once DOAC will be used in clinical practice. This pilot study aims to start a surveillance of a representative sample of non valvular AF patients in Lombardy that will start a new oral anticoagulant therapy (either with DOAC or with AC). Patients with non valvular AF that will start a new antithrombotic therapy will be consecutively selected. It will be possible to include: patients that start an antithrombotic therapy for the first time patients that switch from an antithrombotic therapy to another

Thirtyfive centers joined the study so far: 14 Cardiological unit, 13 Centers for the control of anticoagulant therapy, and 8 Internal Medicine/Geriatric units and the number of patients included is 539.

The stratification of global cardiovascular risk in hypertensive patients of the district of Borbon - Ecuador The Laboratory is involved in a collaborative project with the Cecomet (Centro de Epidemiologia comunitaria y Medicina tropical) in Esmeralda, Ecuador, on the prevalence and treatment of hypertension in the district of Borbon, a rural zone of Ecuador in the northern part of the country. In this area, 36% of the adult population is affected by hypertension and more than half of hypertensive patients present blood pressure levels > 160/110 mmHg. From 2001, in the District is ongoing an intensive follow-up of the hypertensive population with the following aims: to evaluate the global cardiovascular risk of the population, to better control blood pressure levels increasing the number of subjects treated with hypertensive therapy (in particular those at high cardiovascular risk) and monitoring of the clinical complications. Preliminary data show that: patients treated with hypertensive therapy are increased from 39% to 59% antihypertensive drugs are mainly prescribed to subjects with high blood pressure levels (80% of those

with systolic blood pressure >180mmHg are actually under treatment) or at high cardiovascular risk (82%)

blood pressure control is improved (patients with systolic blood pressure levels > 180mmHg decreased from 33% to 24% and those with levels <160-179 increased from 26% to 34%)

the fraction of patients at high or very high cardiovascular risk is decreased from 40% to 33% However, the compliance to antihypertensive treatment is still unsatisfactory since only half of the subjects are compliant with the prescribed therapy.

Laboratory of Medical Statistics The Laboratory of Medical Statistics develops applied research in three main fields: controlled clinical trials, observational studies and genetic epidemiology. Controlled clinical trials The laboratory deals with planning, management and statistical analysis of controlled clinical trials, carried out in the different laboratories of the Department of Cardiovascular Research, by means of the GISSI trials experience. At present, GISSI trials focus on GISSI-HF, GISSI-AF, ALBIOS and OPERA clinical studies, concerning heart failure, atrial fibrillation septic shock and cardiac surgery and their subprojects aiming to assess the role of: new biomarkers, levels of circulating fatty acids, echocardiographic parameters and body weight loss on the patients’ prognosis. At present, the follow-up of patients recruited in the superiority trial BeTACTIC that recruited patients undergone heart transplantation is finalizing the follow-up phase. The main results of the CYCLE study that recruited 410 patients with reperfused acute myocardial infarction have been presented at the italian congress ANMCO in 2015. It’s still ongoing the multicenter trial of superiority in the cardio-oncology field: the ICOS-ONE study is assessing if two different therapeutic strategies can prevent anthracycline cardiotoxicity. The study randomized 273 patients with cancer receiving chemotherapy based on anthracyclines. FINNRESUSCI study recruited patients receiving cardiopulmonary resuscitation and it is evaluating the prognostic value of some biomarkers such as tryptophan, PTX3, kinurenine and copeptin levels to understand their relationship and involvement in the damage post-resuscitation. Concerning the field of cardiovascular prevention, the epidemiological history of the population recruited in the Risk & Prevention study (Rischio & Prevenzione) has been investigated in order to evaluate how the control of modifiable risk factors (smoking, sedentary lifestyle, dietary habits, weight, blood pressure, glycemia, cholesterol) influence the improvement of the overall patient risk profile. Statistical methodology applied to clinical studies has a leading and developing role as far as methods are concerned (e.g.: missing data management; development of prognostic risk scores, methods for the assessment of competing risks, development of forecasting models for biomarkers based on Reclassification techniques, on Discriminations Indices, Restricted Cubic Splines (RSC) analysis, development and application of the Propensity score ).

Moreover, clinical trial management implies the setup of data planning and screening methods, the ad interim analysis and the choice of the best study design (superiority, non-inferiority and equivalence studies). Observational studies The activation of observational studies allows to characterize the epidemiological profile of categories of patients followed in their natural clinical course. The prospective observational study GLICINE-SPIDER has evaluated the risk profile of 1300 patients with hyperglycemia at the onset of an acute coronary syndrome (ACS) in the hospitals of the Lombardia region. The cohort study REGIA, evaluated the incidence of major and minor hemorrhages and the characterization of the risk profile of about 3000 patients undergoing hip and knee replacement surgery. The results of the study have been presented to the researchers and will soon be published. The multicenter study FALCO (Sorveglianza dei pazienti con Fibrillazione Atriale in Lombardia trattati con AntiCoagulanti Orali) recruited 539 patients that will be followed-up to 1 year. Genetic Epidemiology The laboratory has recently developed specific skills on genetic epidemiology analysis. These studies are carried out together with the laboratory of Clinical Drugs Evaluation. Statistical analysis techniques concerning cardiovascular genetics have been developed in the last ten years. The study of the genetic component of multifactorial diseases, such as the cardiovascular disease, has been dealt with in the PROCARDIS study, by means of the genome-wide screening. This technique aims at identifying genes that can cause coronary disease. PROCARDIS database gave the opportunity of studying some quantitative traits such as the level of lipids or body mass index. During the second step of the PROCARDIS project, supported by the 6th Framework Program of EEC, a screening on the whole genome has been carried out by means of the “genome-wide association” technique. For this project about 1 million of polymorphisms (SNPs) have been analyzed in order to identify a possible relationship with coronary disease. Recently, the C4D genetic Consortium, of which the PROCARDIS Consortium takes part, has demonstrated the existence of new susceptibility genes to coronary artery disease (CAD). Indeed CAD is caused by the occurrence of many genes as emerged from recent meta-analyses on GWAS. PROCARDIS study providing the recruitment and genotyping of a large number of healthy subjects, contributed to the investigation of the genetic component of the cerebral stroke participating to the International Stroke Genetics Consortium. The GISSI-HF genetic substudy has included about 2500 patients with the aim to investigate the role of various genetic variants involved in heart failure. Recently the association of five polimorphisms associated to heart failure and to cardiomiopaties has been investigated by a case-control design. At present, the statistical analyses of the GISSI-VAR study (Investigation of patients with BAV requiring valve and/or aortic repair. Correlation of surgical and ECO distinctive features with histologic and genetic findings in phenotypically homogeneous outlier cases) is focused on the identification of potential genetic variants of the known gene NOTCH1 that may result associated to the disease itself as well as to a different severity of the pathology.

Laboratory of Clinical Drug Evaluation BeTACTIC Study: Best Therapy After Cardiac Transplantation, the Italian Challenge BeTACTIC is a multicenter, randomized, no-profit trial funded by the National Health Service. The study compares the efficacy and safety of Everolimus (Ev) and Mycophenolate (MMF) in association with Cyclosporine (CyA) in patients with acute multiple/late rejection, cardiac allograft vasculopathy (CAV), renal dysfunction after cardiac transplantation (HTx). Survival after HTx has improved in the last years, while the attrition rate beyond the 1st year after HTx did not change substantially. CAV and cancer are the leading causes of death late after HTx. Many factors as acute rejections and citomegalovirus infections are involved in CAV pathogenesis. Cancer shows higher incidence in immunosuppressed patients. Significant morbidity/mortality derive from renal insufficiency and vascular complications. Ev and MMF were adopted due to better efficacy vs Azathioprine in de novo HTx. However, Ev and MMF have not been tested in a head to head comparison late after HTx in patients with

CAV. The planned length of the BeTACTIC study is 5 years. Patients will be enrolled at least 1year after HTx. A total of 400 patients will be randomized in 12 Transplant Centers in Italy. BeTACTIC is promoted by the Cardiology Department, Trapianti e Insufficienza Cardiaca, Ospedale Niguarda Ca' Granda, Milano and coordinated by the Laboratory of Clinical Drug Evaluation of the Istituto Mario Negri. ICOS-ONE Study - Prevention of anthracycline-induced cardiotoxicity: a multicentre randomized trial comparing two therapeutic strategies The background and the objectives of the ICOS-ONE study are summarized among the activities of the Laboratory of Cardiovascular Clinical Pharmacology. The Laboratory of Clinical Drug Evaluation is responsible of the organizational and regulatory activities, of the data management and bioinformatics and of the central and on site monitoring of the study. MANAGE Study - Management of myocardial injury After NoncArdiac surGEry Trial. A large, international, randomized, placebo-controlled trial to assess the impact of dabigatran (a direct thrombin inhibitor) and omeprazole (a proton-pump inhibitor) inpatients suffering myocardial injury after noncardiac surgery The Population Health Research Institute (PHRI), McMaster University, Hamilton, Ontario, directed by Professor Salim Yusuf, is the coordinating center of a multinational network of cardiology clinics that collaborate to multicenter large scale clinical trials (nearly 40 Countries and more than 600 cardiology clinics). During the last 20 years the Laboratory of Clinical Drug Evaluation has been responsible for the scientific coordination in Italy of several of these trials (INTER-HEART, CURE, ACTIVE, CURRENT, OASIS-8 FUTURA, RE-LY, AVERROES, RE-LY Registry, RIVAL). The MANAGE study is a multicentre, international, blinded, randomized placebo controlled trial aiming to determine the impact of dabigatran on the risk of a major vascular complication and omeprazole on the risk of a major upper gastrointestinal complication in patients suffering myocardial injury after noncardiac surgery (MINS) and followed on average for 1 year. MINS is the most common major vascular complication after noncardiac surgery. Worldwide approximately 10 million adults annually suffer a perioperative myocardial injury. This figure for perioperative myocardial injury represents 15-20% of all cases of myocardial infarction in all settings. Myocardial injury after noncardiac surgery carries a poor prognosis and is an independent predictor of 30-day and 1-year mortality. The MANAGE Trial will enroll 1700 patients. Studio GISSI Outliers CAPIRE - Coronary Atherosclerosis in outlier subjects: Protective and Individual Risk factor Evaluation The association between known risk factors and ischemic cardiopathy is currently estimated with multivariable prediction models. However, there is a component of individual variability underlying the fact that a relevant number of individuals with multiple risk factors do not progress to coronary atherosclerosis or have clinical events, while others have such events or coronary disease in the absence of risk factors (outliers). The purpose of the CAPIRE study is to identify possible novel protective or risk factors for coronary disease in outlier subjects and generate new etiological hypotheses and therapeutic targets for this disease. This is an observational, multicenter clinical study supported by the Heart Care Foundation in the framework of the GISSI-Outliers program. The Laboratory of Clinical Drug Evaluation is responsible of the assessment of the genetic profile of the outliers patients. The first step is the assessment of the variants of associated to the atherosclerotic disease (e.g. Chr 9p21). Studio GISSI Outliers GISSI-VAR : Investigation of patients with BAV requiring valve and/or aortic repair. Correlation of surgical and ECO distinctive features with histologic and genetic findings in phenotypically homogeneous outlier cases Bicuspid aortic valve (BAV) is the most common congenital heart valve disorder, affecting up to 2% of the population. Only 20% of patients with a congenitally BAV will maintain a normally functioning valve throughout life, while more than 30% of patients will develop serious morbidity. Bicuspid valves are likely

to be the result of a complex developmental process, not simply the fusion of two normal cusps. Several family-based studies have shown that BAV disease, either alone or in combination with other cardiovascular malformations, can be inherited in families, and is therefore likely to have a genetic basis. The aim of this prospective longitudinal study is to select homogeneous small groups of surgical patients with the same subtype of BAV and same aortic behavior and identify markers/predictors of favorable-unfavorable aortic wall evolution to evaluate if there is a BAV phenotype more likely to be considered at high risk for aortic degeneration. The study will focus on multiple aspects of BAV disease: morphology, genetics, histology. The study is supported by the Heart Care Foundation in the framework of the GISSI-Outliers program, with the participation of 11 cardiosurgery departments. The Laboratory of Clinical Drug Evaluation is responsible of the assessment of the genetic profile of the BAV patients. In the first step we did the direct sequencing of NOTCH1 gene in order to identify genetic variants associated to the disease. Blood samples of enrolled patients are stored in our biobank for future research.

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DEPARTMENT OF CARDIOVASCULAR RESEARCH - Mario Negri · Head Giovanna BALCONI, BSc. Laboratory of Cardiopulmonary Pathophysiology Head Giuseppe RISTAGNO, M.D., Ph.D. ... from Mar 2013