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The Role of Heart Rate on Functional Capacity In The role of heart rate on functional capacity in chronic heart failure: association or contribution? Haqeel Ahmed Jamil Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Leeds Institute for Cardiovascular and Metabolic Medicine School of Medicine September 2015 - ii - Intellectual Property and Publication Statements: The candidate confirms that the work submitted is his own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Haqeel Ahmed Jamil to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. © 2015 The University of Leeds and Haqeel Ahmed Jamil - iii - Dedication This thesis is affectionately dedicated to my parents, Mohammed and Azra Jamil for their unremitting love and wisdom, and without whom none of my career would have been possible; to my brothers, Adeel and Nabeel for always providing a mixture of encouragement and welcome distractions; to my wife Sana for her selfless support and understanding throughout: and to my son Zackaria, for the joy he brings to all of our lives. - iv - Acknowledgements I would like to start by thanking my supervisors, Klaus Witte and Mark Kearney for recognising my potential, constantly inspiring me and allowing me the opportunity to undertake research at the Leeds Institute for Cardiovascular and Metabolic Medicine (LICAMM). I would also like to sincerely thank the LICAMM research team and all the staff at the Leeds Cardiac Investigations Unit, for their assistance and support. This research has been carried out by a multi-disciplinary team, which included John Gierula, Roo Byrom-Goulthorpe, Maria Paton, Judith Lowry, Laura Allen, David Cairns and Caroline Bedford. My own contributions, fully and explicitly indicated in the thesis, have been to supervise, design, coordinate and carry out the research studies, as well as the subsequent analyses and discussions. The other members of the group and their contributions have been: exercise test supervision, echocardiography, randomisation, data collection and blinding. I would also like to acknowledge the statistical advice provided by David Cairns (Senior Research Fellow in Biostatistics at University of Leeds), and the support of Caroline Bedford (Lead Pharmacist for Clinical Trials and Medicines Management Services at Leeds General Infirmary) for medication/placebo encapsulation and randomisation services. - v - Finally, I would like to thank all the patients and healthy controls who volunteered for these studies and exercised to exhaustion, thus helping to advance our understanding of how the heart rate contributes to exercise capacity in chronic heart failure. - vi - Abstract A key feature of chronic heart failure (CHF) is an inability of the heart rate (HR) to increase in proportion to the level of physical exertion, known as chronotropic incompetence (CI). Increases in HR during exercise contribute to an increase in cardiac output and hence greater blood supply to exercising peripheral muscles. It is generally assumed therefore that a limitation to heart rate rise might contribute to exercise intolerance. Whether CI is a causal factor in CHF has been a long-standing topic of debate and conflicting opinions. This thesis comprises a series of studies aiming to clarify the role of HR on exercise capacity in CHF. The observational study demonstrated a relationship between exercise capacity and heart rate rise, both of which are reduced in the context of heart failure. I have identified an association between the degree of CI and the extent of exercise capacity reduction in CHF, however this relationship is weaker with more severe CHF. I have also shown in two randomised controlled interventional double-blind crossover trials that increasing or decreasing the heart rate response in patients with CHF, does not result in any changes in exercise capacity. - vii - Finally, in a double blind case-control study, I have demonstrated a marked difference in heart rate related contractility in CHF compared to controls. This suggests that correcting CI may improve exercise capacity in controls by increasing cardiac output via increases in contractility, and this might not be the case in CHF. Based on these novel findings, I conclude that in patients with CHF, CI is a marker of reduced exercise tolerance in CHF, and cannot be considered to be a causal factor. Aggressively correcting CI should therefore not be pursued as part of the the symptomatic treatment of patients with moderate to severe heart failure in either sinus rhythm or atrial fibrillation. Instead the chronotropic adaptation seen with worsening heart failure should be optimised, with the aim to maintain the exertional heart rate rise between 50 to 110 beats per minute. - viii - Table of Contents Dedication .................................................................................................... iii Acknowledgements ..................................................................................... iv Abstract ........................................................................................................ vi Table of Contents ...................................................................................... viii List of Tables .............................................................................................. xv List of Figures ............................................................................................ xvi Preface ..................................................................................................... xviii Chapter 1: Introduction to Heart Failure and Treatment ........................... 1 1.1 Introduction ....................................................................................... 1 1.2 Epidemiology .................................................................................... 3 1.3 Aetiology ........................................................................................... 5 1.4 Systolic Heart failure and diastolic heart failure ............................... 6 1.5 Pathophysiology ............................................................................... 7 1.5.1 Acute compensatory changes ............................................... 7 1.5.2 Chronic structural remodelling .............................................. 8 1.5.3 Neurohormonal adaptation and adverse long term effects ..................................................................................... 8 1.6 Diagnosis ........................................................................................ 11 1.6.1 Signs ................................................................................... 11 1.6.2 Symptoms ........................................................................... 12 1.6.3 Investigations ...................................................................... 13 1.7 Classification .................................................................................. 17 1.8 General treatment .......................................................................... 18 1.9 Pharmacological treatment ............................................................. 19 1.9.1 Diuretics .............................................................................. 19 1.9.2 Angiotensin converting enzyme inhibitors ........................... 21 1.9.3 Angiotensin II Receptor Blockers ........................................ 23 1.9.3.1 Combining ACEi and ARB ....................................... 23 1.9.4 Beta-blockers ...................................................................... 24 1.9.5 Aldosterone antagonists ...................................................... 25 1.9.6 Digoxin ................................................................................ 27 1.9.7 Hydralazine and isosorbide dinitrate ................................... 29 - ix - 1.9.8 Selective sinus node inhibitors (Ivabradine) ........................ 31 1.9.9 Thromboprophylaxis: Antiplatelets and anticoagulation ...... 32 1.9.10 Antiarrhythmic medication ................................................. 33 1.10 Cardiac pacing in heart failure ...................................................... 34 1.10.1 Right ventricular pacing ..................................................... 34 1.10.2 Dual chamber pacing ........................................................ 35 1.10.3 Rate adaptive pacing ........................................................ 38 1.10.4 Implantable cardioverter defibrillator (ICD) as primary prevention ............................................................................ 39 1.10.5 Cardiac Resynchronisation Therapy (CRT) ...................... 40 1.10.6 Left Ventricular Assist Devices (LVAD) and Heart Transplant ............................................................................ 41 Chapter 2: Cardiovascular physiology in health and disease ............... 42 2.1 Cardiac physiological responses during exertion ........................... 42 2.1.1 Cardiac Output .................................................................... 43 2.1.2 Stroke volume ..................................................................... 43 2.1.2.1 Preload ..................................................................... 44 2.1.2.2 Contractility
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