Integrative Human Cardiovascular Control The Panum Institute/ Rigshospitalet, University of Copenhagen 2019 Cerebral blood flow and oxygenation, static and dynamic autoregulation, and relation to orthostatic stress Johannes van Lieshout Internal Medicine & Lab Clinical Cardiovascular Physiology Academic Medical Centre, University of Amsterdam NL School of Life Sciences, University of Nottingham UK
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Beat-to-beat SV: Ultrasound Doppler (bold) and Modelflow ( thin ) Valsalva 150 ABP (mmHg) 100 50 100 SV (%) 50 Pott. JAP 2003 05/04 JJvL 0 20 40 60 5/14/2019 Time (s)
Valsalva maneuver
Valsalva maneuver
Wieling W, Van Lieshout JJ. Clin Auton Res 2002
The ‘fainting lark’ Combining the effects of a) acute arterial hypotension by gravity and b) raised intrathoracic pressure with c) cerebral vasoconstriction in response to hypocapnia
Outline of Presentation – Measurement and Regulation of Cerebral Blood Flow • Techniques and Methodological Issues • What determines Brain Blood Flow? • Static and Dynamic Cerebral Autoregulation and beyond
Cerebral Blood Flow (CBF) and Imaging Techniques • Global CBF (arterial-venous diff N 2 O, 133 Xe, O 2 ) • Magnetic Resonance Imaging (MRI) • MRA (Magnetic Resonance Angiography & Venography) • Regional CBF (Ultrasound - Transcranial Doppler) • Single-Photon Emission Computed Tomography (SPECT) • Positron Emission Tomography (PET) • SPECT/CT and PET/CT, Near-Infrared Spectroscopy
Measurement of Global Cerebral Circulation - Inert Gas Nitrous Oxide Kety and Schmidt, J Clin Invest 1948
Fick Principle • Systemic circulation: VO 2 = CO * (C a – C v ) • Cerebral circulation: CMRO 2 = CBF * (C a – C v jug )
Ohm’s Law voltage (V) = amperage (I) * resistance (R) CPP = CBF * CVR Cerebral Perfusion Pressure Cerebral Blood Flow Cerebral Vascular Resistance Applied to TransCranial Doppler Ultrasonography MAP = CBFV * CVR Mean Arterial Pressure Cerebral Blood Flow Velocity Cerebral Vascular Resistance at brain level
Transcranial Doppler Cerebral Blood Flow Velocity
Assessment of Cerebral Perfusion • TCD middle cerebral artery blood velocity pro: - beat-to-beat evaluation of (regional) CBF con: - larger changes in arterial distending pressure may affect MCA diameter with under / overestimation of CBF - heterogeneity in cerebral vascular responsiveness
Limitations • transcranial Doppler cerebral artery velocity is taken as 'a surrogate' for CBF • cerebral blood flow/velocity is the outcome measure, and a relationship to vascular control is only inferred • arterial pressure may not fully reflect CPP (the pressure driving CBF in the large cerebral arteries)
Reviewer’s comment: Constant diameter under the conditions of the study? ?
Verbree et al. JAP 2014
7T MRI evaluation of Middle Cerebral Artery during Rhythmic Handgrip Exercise Sympathetic activation by handgrip exercise reduces MCA cross-sectional area Verbree J, Bronzwaer AS, van Buchem MA, Daemen MJAP, Van Lieshout JJ, Van Osch MJ. J Cereb Blood Flow Metab 2016
Brain vascular control during exercise ▪ Effects of exercise on cerebral metabolism are highly heterogeneous ▪ Increases in CBF are not global but localized to specific areas of the brain Lassen NA, Ingvar DH and Skinhoj E. Brain Function and Blood Flow. Sci Am. 1978;239:62-71
Limitations to be considered • arterial pressure may not fully reflect the pressure driving CBF in the large cerebral arteries • transcranial Doppler cerebral artery velocity is taken as 'a surrogate' for CBF • cerebral blood flow/velocity is the outcome measure, and a relationship to vascular control is only inferred
Outline of Presentation – Measurement and Regulation of Cerebral Blood Flow • Techniques and Methodological Issues • What determines Brain Blood Flow?
• Which influences for brain blood flow? - brain activation (visual stimulation, exercise) - metabolic (from rest to exercise) - chemical - PaCO 2 , O 2 - autoregulation - neurogenic - sympathetic system influence - endothelial cell smooth muscle cell - ATP, adenosine, brain-derived neurotrophic factor (BDNF) - cardiac output - ageing
Control of Cerebral Circulation in Health and Disease Lassen NA. Autoregulation of cerebral blood flow. Circ Res 15: 201-204, 1964
• CHEMICAL (PaCO 2 , PaO 2 ) HYPERVENTILATION 200 BP (mm Hg) 100 0 150 -1 ) MCAV (cm·s 75 0 30 P ET CO 2 (mm Hg) 15 0 0 30 60 Time (s)
Cerebral Responsiveness to Carbon Dioxide (CO 2 reactivity of the brain) Ide K, Eliasziw M, and Poulin MJ. J Appl Physiol 95: 129-137, 2003
• Activation Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 1976
Cerebral blood flow during exercise in T2DM Activation of the brain by exercise enhances CBF ❖
• Changes in MCA V mean during exercise are similar to those recorded with the initial slope index of the 133 Xe clearance method • During heavy dynamic exercise, MCA V mean increases 24 (10-47)% Jorgensen LG, Perko M, Hanel B, Schroeder TV and Secher NH. Middle Cerebral Artery Flow Velocity and Blood Flow During Exercise and Muscle Ischemia in Humans. J Appl Physiol. 1992;72:1123-1132
Effects of exercise intensity and duration on indices of cerebral blood flow and oxygenation during exercise Laughlin MH, Davis MJ, Secher NH, van Lieshout JJ, Arce-Esquivel AA, Simmons GH, Bender SB, Padilla J, Bache RJ, Merkus D and Duncker DJ. Peripheral Circulation. Compr Physiol. 2012;2:321-447.
Relationship cardiac output and MCA V from rest to exercise Reductions in Q accomplished by lower body negative pressure (LBNP), increases in Q by infusions of 25% human serum albumin Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN, Purkayastha S, Yurvati A and Raven PB. J Physiol. 2005;569:697-704.
Effects of Exercise on CBF in Heart Failure • With one-legged exercise CBFV is maintained but declines with two-legged exercise Hellstrõm G, Magnusson G, Wahlgren NG, Saltin B. Physical exercise may impair cerebral perfusion in patients with chronic heart failure. Cardiol Elderly 1996
• AGEING ~15% reduction in gray matter flow between the 3rd and 5th decade Shaw TG, Mortel KF, Meyer JS, Rogers RL, Hardenberg J, Cutaia MM. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology 1984 Meyer JS, Terayama Y, Takashima S. Cerebral circulation in the elderly. Cerebrovasc Brain Metab Rev 1993
• BODY POSITION Bode H. Eur J Pediatr 1991 Levine BD, et al. Circulation 1994 Bondar RL, et al. Stroke 1995 Schondorf R, et al. Stroke 1997 Novak V, et al. Stroke 1998 Lipsitz LA, et al. Stroke 2000 Van Lieshout JJ, et al. Stroke 2001 Harms MPM, et al. Stroke 2000 Pott F, et al. JAP 2000 Alperin N, et al. J. Magn Reson Imaging 2005
Postural reduction in central blood volume affects the brain • Assumption of the upright position carries the head above heart level BP at brain level ~ 20 mmHg Cardiac output 20-30% PCO 2 Cerebral Blood Velocity 15% Brain takes 15-20% of cardiac output
Middle cerebral artery blood velocity declines when standing Standing 100 MCA V mean -1 ) (cm.s 50 150 100 MAP (mmHg) 50 0 30 60 Time (s) Van Lieshout JJ, Pott F, Madsen PL, Van Goudoever J, Secher NH. Stroke 32: 1546-1551, 2001
Outline of Presentation – Measurement and Regulation of Cerebral Blood Flow • Techniques and Methodological Issues • What determines Brain Blood Flow? • Static and Dynamic Cerebral Autoregulation
Cerebral Autoregulation in Healthy Subjects 130 130 Blood Pressure (%) 120 120 MCAV (%) 110 110 100 100 90 90 0 1 2 3 4 5 6 7 8 9 10 Time (s)
Effect of Dynamic Exercise on Blood Pressure What will brain blood flow do? Rasmussen P, Plomgaard P, Krogh-Madsen R, Kim YS, Van Lieshout JJ, Secher NH, Quistorff B. J Appl Physiol 2006;101:1406 Kim YS, Krogh-Madsen R, Rasmussen P, Plomgaard P, Ogoh S, Secher NH, van Lieshout JJ. Am J Physiol Heart Circ Physiol 2007;293:H467
… and on Cerebral Blood Velocity autoregulation malfunction ? Rasmussen P, Plomgaard P, Krogh-Madsen R, Kim YS, Van Lieshout JJ, Secher NH, Quistorff B. J Appl Physiol 2006;101:1406 Kim YS, Krogh-Madsen R, Rasmussen P, Plomgaard P, Ogoh S, Secher NH, van Lieshout JJ. Am J Physiol Heart Circ Physiol 2007;293:H467
Static and Dynamic Components of Cerebral Autoregulation (CA) Static CA Q reflects the overall efficiency of the system P Dynamic CA ability to restore cerebral blood flow within seconds in response to BP changes reflects latency of regulatory system
Cerebral Autoregulation In biological systems reflex gain is not infinite Cerebral CVRI CBF vasoconstriction Cerebral vasodilation 60 150 60 150 Perfusion Pressure Perfusion Pressure mmHg mmHg Courtesy of Eubank and Raven
Dynamic Cerebral Autoregulation - Assessment • Inducing a fall in mean arterial pressure (cuff release; Aaslid manoeuvre) • Rest and steady-state orthostatic stress Spontaneous and induced oscillations
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