Some pages of this thesis may have been removed for copyright restrictions. If you have discovered material in Aston Research Explorer which is unlawful e.g. breaches copyright, (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown policy and contact the service immediately ([email protected]) T U O S O R V A I O P C J D F Doctor of Philosophy A U September 2019 © Christian James Doro French, 2019 Christian James Doro French asserts his moral right to be identified as the author of this thesis. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright belongs to its author and that no quotation from the thesis and no information derived from it may be published without appropriate permission or acknowledgement. 1 Aston University The Use of Static Retinal Vessel Analysis in Optometric Practice Christian James Doro French Doctor of Philosophy 2019 Thesis summary: At present optometric examination of the retinal microcirculation consists of a subjective assessment of artery size when compared to a neighbouring vein; the arterio-venous ratio (AVR). Despite it’s documented limitations, the AVR still features in UK optometric clinical guidance. An objective method of recording the central retinal artery and vein equivalent sizes (CRAE and CRVE) has been used for research purposes for two decades but has yet to be validated in a clinical setting. A review of the present literature identified correlations between CRAE and CRVE and three key cardiovascular pathologies; hypertension, diabetes mellitus and stroke. A methodological study was undertaken to establish whether retinal photographs acquired in clinical practice yielded results with reproducib- ility comparable with those in the literature. It was shown that calibre measurements do not fluctuate significantly with the use of mydriatics, or subject to minor temporal fluctuations. When the technique was applied in clinical practice, a cross-sectional cohort (n = 271) revealed vessel correlations with systemic biomarkers in agreement with those identified in the literature review. CRAE was seen to be reduced in those with raised blood pressure, and objective AVR was reduced in those with increased cardiovascular risk (QRISK). There did not appear to be signi- ficant fluctuations in vessel measurements when the cohort was observed longitudinally across a period of 12 – 24 months, suggesting changes either too slow or too small to be detected at present; supporting theories of gradual morphological changes. When considered as part of scope of primary care, improved cardiovascular assessment through retinal vessel analysis (especially when supplemented with blood pressure and cardiovascular risk calcula- tions) relieves pressure on GPs and identifies a significant number of previously undiagnosed and unmanaged cases of cardiovascular disease. The results build a strong case for the incorporation of objective retinal vessel analysis into routine optometric clinical guidelines. Keywords: Optometry, Retinal Vessels, Cardiovascular Disease, Multi-disciplinary Care 2 Dedication I would like to extend my thanks and appreciation to a number of individuals who have contributed, supported or assisted throughout the development of this thesis. Firstly, to the staff at Aston University; particularly Richard Armstrong for his invaluable help with the intricate world of statistics and Rob Cubbidge, for his insight and support throughout. Next, I would like to thank my colleagues at the University of Hertfordshire; Joy, Lynne, Amy, Sheila and the rest of the team for their help and support with getting this manuscript finished whilst juggling my lecturing commitments. I would also like to thank Davis Optometrists, particularly my willing and enthusiastic patients, who kindly gave up their time to provide their data; this PhD would not have been possible without them. Nor would it have been possible without the financial support from the College of Optometrists; I am very thankful for the opportunity they have given me. I am immensely grateful to the team at Imedos; Cornelia, Benedikt, Walthard, Volker and the rest of the team who have helped provide valuable technical insight and support, making me feel extremely welcome in the process. To my wonderful family, particularly my parents who have always supported me and taught me to do what makes me happy, and my friends; both those going through the same PhD stresses (Katrin, Emma and Maryam), and those who could provide the much needed distractions from a seemingly endless workload (Aiden, Emily, Will and Matt). I would also thank Bill, Lee, John and the other members of CADSAC for introducing me to the joys of scuba diving. Finally, I would like to extend my heartfelt thanks to my supervisor, Rebekka, for her continued friendship, encouragement and support throughout; the PhD has been an incredible experience and I look forward to the research that lies ahead. 3 Contents 1 Introduction 16 1.1 Overview . 16 1.2 Projected Impact of Cardiovascular Disease . 16 1.3 Overview: Hypertension . 17 1.4 Overview: Diabetes Mellitus . 22 1.4.1 Type I diabetes mellitus . 22 1.4.2 Type II diabetes mellitus . 22 1.4.2.1 Young-onset Type II diabetes mellitus . 23 1.4.3 Diagnosis . 23 1.4.4 Monitoring . 24 1.4.5 Systemic complications of diabetes mellitus . 25 1.4.6 Ocular complications of diabetes mellitus . 25 1.4.6.1 Non-proliferative diabetic retinopathy . 25 1.4.6.2 Proliferative diabetic retinopathy . 27 1.4.6.3 Diabetic macular oedema . 27 1.5 Overview: Stroke . 28 1.6 The Cardiovascular System: gross anatomy . 28 1.7 Vascular supply to the ocular circulation: The Central Retinal Artery . 29 1.8 Vascular drainage from the ocular circulation: The Central Retinal Vein . 33 1.9 Subjective Retinal Vessel Calibre Assessment . 33 1.9.1 Subjective Measuring . 34 1.9.1.1 Arterio-Venous Ratio . 34 1.9.1.2 Subjective-Objective Measuring . 35 1.9.2 Subjective Grading . 37 1.9.2.1 Keith-Wagener-Barker Classification . 37 1.9.2.2 Scheie Modification . 39 1.9.2.3 Neubauer Classification . 39 1.9.2.4 Dodson et al. Prognosis-based Classification . 40 1.9.2.5 Mitchell and Wong Simplified Classification . 40 1.10 Objective Retinal Vessel Calibre Formulae . 42 4 1.10.1 Parr & Spears . 43 1.10.2 Hubbard et al. 44 1.10.3 Knudtson et al. 45 1.10.4 Future formulae . 47 1.11 Study Hypotheses and Aims . 47 2 Associations of Retinal Vessel Calibre with Cardiovascular Disease: A Systematic Literat- ure Review 49 2.1 Introduction . 49 2.2 Methods . 49 2.2.1 Inclusion criteria . 50 2.2.2 Exclusion criteria . 50 2.2.3 Study Selection & Data Processing . 50 2.3 Results . 51 2.4 Discussion . 62 2.4.1 Association of blood pressure and retinal vessel calibre . 62 2.4.2 Association of diabetes mellitus and retinal vessel calibre . 64 2.4.2.1 Incident diabetes . 65 2.4.2.2 Existing diabetes mellitus and diabetic retinopathy status . 66 2.4.2.3 Existing diabetes mellitus and systemic complications . 68 2.4.3 Association of stroke and retinal vessel calibre . 70 2.4.4 Conclusions . 73 3 Materials & Methods 75 3.1 Image Acquisition . 75 3.1.1 Fundus photography . 75 3.1.2 Correction factors . 77 3.1.3 Fundus photography protocol for current study . 80 3.2 Image Analysis . 81 3.2.1 Vessel selection . 81 3.2.2 Software available . 81 3.2.3 Image analysis protocol for current study . 83 5 3.2.4 VesselMap protocol . 87 3.3 Sample size and patient recruitment . 90 3.3.1 Sample size for the present studies . 91 3.3.2 Patient recruitment . 92 3.4 Additional ocular parameters . 92 3.4.1 Tonometry . 92 3.4.1.1 Tonometry protocol for current study . 93 3.4.2 Refraction . 93 3.4.2.1 Refraction protocol for current study . 93 3.5 Cardiovascular metrics . 94 3.5.1 Sphygmomanometry . 94 3.5.1.1 Sphygmomanometry protocol for current study . 94 3.5.2 Pulse Oximetry . 95 3.5.2.1 Pulse Oximetry protocol for current study . 97 3.5.3 Cardiovascular Risk Calculators . 97 3.5.3.1 Cardiovascular Risk Calculator protocol for current study . 98 4 Repeatability and Variability in Objective Static Retinal Vessel Calibre Measurement 100 4.1 Introduction . 100 4.2 Methods . 103 4.2.1 Effect of dilation . 103 4.2.2 Sequential imaging . 104 4.2.3 Repeated imaging . 104 4.2.4 Image analysis . 104 4.2.5 Statistical.