Treibel TA, PhD Thesis 2017 Aortic Stenosis – a Myocardial Disease SystemicInsights from amyloidosis Myocardial Tissue by Cardiovascular Characterisation Magnetic Resonance Dr MariannaPhD Thesis Fontana Dr Thomas Alexander Treibel PhD Thesis UCL UCL Cardiovascular Sciences 20152017 1 Page 1 of 193 Treibel TA, PhD Thesis 2017 Declaration I, Thomas Alexander Treibel, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature................................................................................................................ Name: Thomas A. Treibel Date ........................................... Page 2 of 193 Treibel TA, PhD Thesis 2017 For Elouisa Page 3 of 193 Treibel TA, PhD Thesis 2017 Abstract Aortic stenosis (AS) is a disease of not just the valve, but also of the myocardium. Patient symptoms and outcome are determined by the myocardial response; a crucial but poorly understood process. Diffuse and focal myocardial fibrosis play a key role. Until recently, both could only be assessed using invasive histology, but now cardiovascular magnetic resonance (CMR) offers late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) techniques. In this thesis, I developed new methods to quantify ECV by synthetic ECV and cardiac CT. I then explored myocardial remodelling and fibrosis in patients with severe AS undergoing aortic valve replacement (AVR) using myocardial biopsy, CMR, biomarkers and a wide range of clinical parameters. Prior to AVR, CMR in patients with severe AS revealed important differences in myocardial remodelling between sexes, otherwise missed on echocardiography alone. Given apparently equal valve severity, the myocardial response to AS appeared unexpectedly maladaptive in men compared to women. Intra-operative myocardial biopsy revealed three pattern of fibrosis: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Biopsy best captured the transmural gradient of fibrosis and microscars, while on CMR, LGE captured mainly microscars and ECV captured mid-myocardial related functional changes beyond LGE. Combining LGE and ECV allowed better stratification of AS patients. Incidentally, I found that 6% of AS patients older then 65 years had wild-type transthyretin amyloid deposits on cardiac biopsy, which was associated with poor outcome. This is now the basis of a BHF research fellowship. Following AVR, I demonstrated for the first time non-invasively that diffuse fibrosis regresses (focal fibrosis did not), which is accompanied by structural and functional improvements suggesting that human diffuse fibrosis is plastic, measurable by CMR and a potential therapeutic target. Funding This work was funded by a doctoral research fellowship from the National Institute for Health Research (DRF-2013-06-102) to whom I am extremely grateful. Page 4 of 193 Treibel TA, PhD Thesis 2017 Acknowledgments I would like to thank the subjects and patients who took part in the studies that constitute this thesis. Without their generous cooperation and help I would not have been able to successfully progress through the different stages of this project. I would like to acknowledge and thank the following people: In particular I would like to thank my supervisor Prof James Moon for his expert guidance, constructive criticism, enthusiasm and encouragement over the last 4 years. The unique environment he set up at the Heart Hospital Imaging Centre was crucial for the success of my project. I would also like to thank my secondary supervisor Prof Stuart Taylor for his input into the CT aspects of my project and for his support during my upgrade. The collaboration with his team, in particular Dr Steve Bandula, was key for the development of the CT ECV methodology at UCL. Importantly, I would like to thank the fellows at the Heart Hospital, colleagues and friends – the team work and joint ideas have enable our joint achievements: Marianna Fontana, Steve White, Dan Sado, Rebecca Kozor, Rebecca Schofield, Katia Menacho, Stefania Rosmini, Silvia Castelletti, Anish Bhuva, Paul Scully, Sanjay Banypersad, Andy Flett, Viviana Maestrini, Amna Abdel-Gadir, Arthur Nasis, Maria Espinoza, Patrizia Reant, Sabrina Nordin, Camilla Torlasco, Guilia Benedetti. I would also like to thank Dr Anna Herrey, Dr Charlotte Manisty, Sarah Anderson, Jodee Cooper, Louise McGrath and especially our never-stopping Sandy Gardner. I would like to acknowledge the contributions of the, theatre, nursing and administrative staff, physiologists, radiographers and biomedical scientists at the Barts Heart Centre and the University College London Hospitals. I grateful to the cardiothoracic team at the Heart Hospital for their support of my project and for obtaining the myocardial biopsy, in particular the cardiothoracic surgeons Martin Hayward, John Yap, Shyam Kolvekar, David Lawrence, Carmelo diSalvo, Amir Sheikh, Neil Roberts and Prof Christopher McGregor. I would also like to thank Dr Petros Syris, UCL, for helping me in biopsy and biomarker logistics. Page 5 of 193 Treibel TA, PhD Thesis 2017 I would like to thank the team at the department at Histopathology, Great Ormond Street Hospital for their technical expertise and high quality input into my project, in particular Dr Michael Ashworth and Tobias Hunt. I would like to thank the team a the National Amyloidosis Centre for their support, knowledge and patience, in particular Prof Philip Hawkins, Janet Gilbertson, Thirusha Lane, Dr Julian Gillmore, Dr Helen Lachmann, Dr Carol Whelan and Dr Ashutosh Wechalekar, as well as the clinical and administrative staff. I would like to thank Drs. Stefan Piechnik, Peter Kellman, Matt Robson, and Vivek Muthurangu for physics support and advice during technical development, and Prof Alun Hughes, Dr Guy Lloyd, Dr Francesca Pugliese and Dr Erik Schelbert for guidance and advice in the preparation of manuscripts. I would also like to thank my collaborators in Pamplona, Prof Javier Díez, Dr Arantxa Gonzales and Dr Begoña Lopes, as well as the whole team at CIMA. Lastly and most importantly, I would like to thank my wife Lucy for her support, patience and tolerance during these last 4 years. Page 6 of 193 Treibel TA, PhD Thesis 2017 Abbreviations 6MWT = 6-minute-walk test ACE-I = angiotensin-converting-enzyme inhibitor AF = atrial fibrillation AL = immunoglobulin light-chain amyloid ARB = angiotensin-receptor blocker AS = aortic stenosis ATTR = transthyretin amyloid AVAi = aortic valve area index AVR = aortic valve replacement BMI = body mass index; BSA = body surface area CABG = coronary artery bypass graft CAD = coronary arterial disease CMR = cardiovascular magnetic resonance CCT = cardiac computed tomography CVF = collagen volume fraction DBP = diastolic blood pressure ECV = extracellular volume fraction eGFR = estimated glomerular filtration rate ECM = extracellular matrix EDVi = end-diastolic volume index ESVi = end-systolic volume index EuroScoreII = European System for Cardiac Operative Risk Evaluation II Gd-DTPA = Gadolinium-diethylenetriamine penta-acetic acid HCM = hypertrophic cardiomyopathy HCT = haematocrit HFpEF = heart failure with preserved ejection fraction HHF = hospitalisation for heart failure hs-TnT = high sensitivity troponin T HTN = hypertension HU = Hounsfield units IQR = interquartile range LAAi = left atrial area index LGE = late gadolinium enhancement LVEF = left ventricular ejection fraction LVH = left ventricular hypertrophy LVMi = left ventricular mass index LVEF = left ventricular ejection fraction MAPSE = mitral annular plane systolic excursion MOLLI = MOdified Look-Locker Inversion recovery MOCO = motion correction NT-proBNP = N-terminal pro-brain natriuretic peptide NYHA = New York Heart Association SBP = systolic blood pressure ShMOLLI = Shortened MOdified Look-Locker Inversion recovery STS = Society of Thoracic Surgeons' risk model score TAVI = transcatheter aortic valve implantation TTR = transthyretin Page 7 of 193 Treibel TA, PhD Thesis 2017 Table of Contents Declaration ................................................................................................................. 2 Abstract ...................................................................................................................... 4 Acknowledgments ...................................................................................................... 5 Abbreviations ............................................................................................................. 7 Table of Contents ....................................................................................................... 8 Table of Tables ........................................................................................................ 10 Table of Figures ....................................................................................................... 11 Chapter 1 Introduction ........................................................................................... 14 1.1 Aortic stenosis ............................................................................................. 14 1.2 Current dilemmas in the management of AS ............................................... 24 1.3 Myocardial Tissue Characterisation by CMR .............................................. 25 1.4 T1 Mapping and Diffuse Myocardial Fibrosis .............................................. 33 1.5 Myocardial tissue characterisation