Dedication: To my parents for all Your love, care and support! List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Järhult, S.J., Hall, J., Lind, L. (2008) Hyperemic blood-flow velocities in systole and diastole relate to coronary risk in divergent ways. Clinical Physiology and Functional Imaging 28(3)189-95 II Järhult, S.J., Sundström, J., Lind, L. (2009) Brachial artery hyperemic blood-flow velocities are related to carotid atherosclerosis. Clinical Physiology and Functional Imaging 29(5):360-5. III Järhult, S.J, Sundstrom, J, Lind, L. Brachial artery hyperemic blood flow velocity and left ventricular geometry. Submitted. IV Järhult, S.J, Hansen, T., Ahlström, H., Johansson, L., Sundström, J., Lind, L. Brachial artery hyperemic blood flow velocity in relation to established indices of vascular function and global atherosclerosis. Submitted. Reprints were made with permission from the respective publishers. Contents Introduction...................................................................................................13 The cardiovascular system............................................................................14 Structure, function and main regulation...................................................14 Atherosclerosis..............................................................................................17 Risk factors for cardiovascular disease.........................................................19 Scoring systems........................................................................................20 The Framingham Risk Score (FRS) ....................................................20 The SCORE-CARD evaluation system ...............................................20 CV risk markers ............................................................................................21 Carotid artery............................................................................................21 Carotid compliance..............................................................................21 Carotid plaques ....................................................................................22 Carotid plaque echogenicity ................................................................22 Carotid intima media thickness (IMT) ................................................22 Left ventricular hypertrophy (LVH).........................................................22 The endothelium ...........................................................................................24 Nitric Oxide (NO) in endothelial function ...............................................24 Evaluation of endothelial function ...........................................................24 EDV and EIDV....................................................................................25 Flow Mediated Dilation.......................................................................25 Arterial stiffness............................................................................................26 Methods aiming to assess arterial stiffness ..............................................26 Pulse Wave Velocity............................................................................26 Pulse Wave Reflection.........................................................................26 Central Pulse Wave analysis................................................................27 Stroke volume to pulse pressure (SV/PP) ratio ...................................27 Carotid artery distensibility .................................................................27 Imaging methods......................................................................................27 Ultrasonographic imaging ...................................................................27 The Doppler principle..........................................................................28 Magnetic Resonance Imaging (MRI) ..................................................28 X-ray angiography...............................................................................28 Computed Tomography (CT) and Positron Emission Tomography, (PET) ...................................................................................................28 Physiology of ischemia and hyperemia ........................................................29 Blood flow................................................................................................29 Vascular resistance...................................................................................29 Reactive hyperemia..................................................................................29 Shear stress...............................................................................................30 Flow patterns in the Brachial artery .........................................................30 Hyperemic blood flow in the Brachial artery................................................32 Technical aspects of evaluating Brachial hyperemia by FMD.................33 Method.................................................................................................33 Preconditions and pitfalls of correct FMD evaluation.........................33 Blood flow velocity .............................................................................34 Blood flow velocity in hyperemia of the Brachial artery.........................34 Rest vs. hyperemia...............................................................................34 VTI.......................................................................................................35 Systolic and diastolic blood flow velocity...........................................35 Overall aim...............................................................................................38 Specific aims: ...........................................................................................38 Material and methods....................................................................................39 Participants...............................................................................................39 Methods....................................................................................................41 Brachial artery monitoring...................................................................41 Carotid artery imaging.........................................................................43 Echocardiography................................................................................44 The invasive forearm technique...........................................................45 Carotid artery compliance....................................................................45 Stroke volume to pulse pressure ratio..................................................46 Pulse wave analysis .............................................................................46 Total peripheral resistance...................................................................46 Magnetic resonance angiography ........................................................46 Statistical analysis................................................................................49 Results and discussion ..................................................................................50 Paper 1......................................................................................................50 Results .................................................................................................50 Discussion............................................................................................53 Paper 2......................................................................................................55 Results .................................................................................................55 Discussion............................................................................................56 Paper 3......................................................................................................57 Results .................................................................................................57 Discussion............................................................................................60 Paper 4......................................................................................................61 Results .................................................................................................61 Discussion............................................................................................64 General discussion/ Summary.......................................................................66 Sammanfattning på svenska..........................................................................68 Acknowledgements.......................................................................................71 References.....................................................................................................73 Abbreviations Ach Acetylcholine Aix Augmentation index AMI Acute myocardial infarction BFI Blood flow increase BP Blood pressure CCAD Common carotid artery distensibility CRP C-reactive protein CV Cardiovascular C.V Coefficient of variation CVD Cardiovascular disease CT Computed tomography DBP Diastolic blood pressure ECG Echocardiogram EDV Endothelium dependent vasodilatation EIDV Endothelium independent vasodilatation FMD Flow mediated vasodilation FRS Framingham Risk Score GSM Grey