Arterial Stiffness: pathophysiology and clinical impact Gérard M. LONDON Manhès Hospital Fleury-Mérogis/Paris, France
Determinants of vascular overload (afterload) on the heart Peripheral Resistance Arterial Stiffness Wave reflection Inertance
Arterial Impedance as a determinant of afterloadgradients Zc P f Z P R P t b PWV= Zc Aorta Z R Resistance vessels STIFFNESS RESISTANCE REFLECTION Reflection Coefficient = Zr -Zc- Zr - Zc + Zc-characteristic impedance Zr-peripheral resistance
mm Hg 140 Systolic pressure Mean BP Pulse pressure 80 Mean BP: Cardiac output peripheral resistance Diastolic pressure Pulse pressure: ventricular ejection arterial stiffness wave reflection
Pressure Flow-Pressure relationship - influence of the fraquency (Resistance = slope of the relationship) Steady -mean flow Pulsatile flow 1 Hz Pulsatile flow 2 Hz Pulsatile flow 3 Hz Flow R=8. L/r 4 (-viscosity; L length; r= radius - number of vessels) R= Mean Blood Pressure/Cardiac output
Flow (ml/min) Pressure-flow relationship - influence of the fraquency (Resistance = slope of the relationship) Ringer Blood Blood + Noradrenaline Autogegulation Perfusion pressure (mm Hg)
VOLUME Diagrammatic representation of volume-pressure relationship P V Transition zone V/P=Compliance P/V=Elastance (Stiffness) PRESSURE
Volume Pressure Diagrammatic representation of volume-pressure relationship V/P=Compliance P/V=Elastance (Stiffness) P P V Transition zone V P V Pressure Volume
The arterial wall is a heterogeneous material Distensible balloon (rubber=elastin) Rigid/stiff net (steel=collagen) A.Tedgui and B. Levy, 1994
The arterial wall is a heterogeneous material A.Tedgui and B. Levy, 1994
Pressure Diagrammatic representation of pressure-volume relationships Einc=2 Einc=1 dp/dv Volume
Blood pressure Blood pressure Arterial function and blood pressure Pure Conduit Function Conduit and Cushioning Function Mean pressure Mean pressure Systole Diastole Systole Diastole
Blood pressure Relationship of Resistance (R) and Compliance (C) with diastolic pressure decay 140 = R.C =1/ = 1/R.C * log scale -time constant of diastolic decay 80 -slope of diastolic decay 4.6 4.38 Adapted from Simon et al. Am J Physiol 1979 Blood pressure *.................... Time (sec)
The diameter-pressure curve 7.3 diameter (mm) Diameter (mm) 7.30 Local pressure 150 7.2 7.1 7.15 125 100 7 0 1 Time (sec) High-definition echotracking devices Wall Track system NIUS system 7.00 70 90 110 130 150 75 0 1 Time (sec) Aplanation Tonometry Millar Instruments
Arterial Diameter (mm) Pressure-diameter relationship : a thermodynamic analysis 2.8 Viscosity = Dissipated energy 2.6 2.4 Distensibility = Exchanged energy 2.2 70 90 110 130 150 Arterial Pressure (mm Hg)
Pressure/arterial luminal cross-sectional area and hysteresis loop in vivo before and after desendothelisation Desendothelisation Intact endothekium Boutouyrie P et al. Arterioscler Thromb Vasc Biol 1997;17:1346-55
Carotid-femoral pulse wave velocity PWV=L/t t L PWV²=Einc*IMTh/D
Aortic PWV (cm/s) Correlation between common carotid artery (CCA) distensibility and aortic pulse wave velocity (PWV)in human population 2500 2090 1680 r=-0.825 p<0.0001 1270 860 450 0 20 40 60 CCA distensibility (kpa 10-1.10-3 )
W W Nichols & M O Rourke, Mc Donald s blood flow in
Pressure wave analysis measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity
Effect of arterial stiffness on timing of forward and reflected Waves PWV 8 m/sec PWV 12 m/sec Negative Aix Positive Aix Systolic Augmentation Pressure (Aix). T T Forward-traveling wave Backward-traveling reflected wave Actual (composite) wave T - traveling time of pressure wave to reflecting sites and back
Aortic versus Peripheral pulse pressure Aorta amplification Peripheral Artery Energy dissipation. T Forward-traveling wave Backward-traveling reflected wave Actual (composite) wave T - traveling time of pressure wave to reflecting sites and back
(mm Hg) (mm Hg) (mm Hg) Pressure Waves Recorded Along the Arterial Tree Maximum Early Wave Reflection 150 100 50 150 100 50 Age 68 years Age 54 years Maximum Amplification 150 100 50 Renal artery Age 24 years Femoral artery Thoracic aorta Abdominal aorta Iliac artery Ascending aorta Nichols WW, et al. Arterial Vasodilation. Philadelphia,1993;32.
Aortic (carotid) pressure waveforme P= augmented pressure P PP=pulse pressure Augmentation index=p/ PP Tsh= time to shoulder LVET=left ventricular ejection time PP Tsh. Tsh LVET Forward- wave Reflected wave Actual wave
Time to shoulder (TSh ms) Relationship between the time of appearance of reflected wave on the pressure wave in central artery (time to shoulder - TSh) and aortic pulse wave velocity (PWV) 225 190 155 R=-0.671 p<0.0001 120 85 50 500 825 1150 1475 1800 aortic PWV (cm/s)
Time to shoulder (TSh ms) Relationship between the time of appearance of reflected wave on the pressure wave in central artery (time to shoulder - TSh) and body height 225 190 R=0.585 p<0.0001 155 120 85 50 130 140 150 160 170 180 190 200 Body height (cm)
Arterial Impedance Gradients Zc-characteristic impedance; Zr-peripheral resistance Reflection Coefficient ( ) = Z Z R R - Z + Z C C = P P b f Zc P b P f Z R P t PWV=6 m/s PWV=10 m/s Pb P f P t PWV=12 m/s PWV=11 m/s Aorta Muscular arteries Resistance vessels
Fourier series - the mean terma and first 6 harmonics of a presure wave from ascending aorta (Westerhof et al 1979) Pressure = 0+P1+P2+P3 = a1 cos(t+1) + a2 cos(t+2)+ a3 cos(t+3)...
Pressure and flow waves broken down into mean term and Fourier series Modulus is the amplitude of pressure harmonic divided by the amplitude of corresponding flow harmonic, and phase as the delay between corresponding harmonics
Modulus and phase of impedance in the ascending aorta McDonald blood flow in the arteries 1994
Schematic representation of vascular impedance (Modulus= Pressure/flow) Peripheral resistance (Zr) Modulus (dynes sec cm-5) 1500 1000 500 First minimum of impedance modulus - f min (lowest pressure for a given flow) Characteristic impedance Zc 0 0 1 2 3 4 5 6 7 (Heart rate) Frequency (Hertz)
Pressure and flow waves along the tubular model completely occluded. At the closed end the pressure is maximal and flow zero. The best coupling minimal pressure for maximal flow is at 1/4 of the wavelength ( =PWV/frequency ) equal to the distance L to site of reflection Flow Pressure L=/4 Best coupling L=/4=PWV/4f fmin=1/2 tp T L = PWV* tp/2 Exemple: tp = 0.125s, 2 tp=0.25s, fmin=1/0.25=4hz
First minimum of impedance (Hz) Relationship between the first minimum of impedance modulus and body height 9.0 8.0 7.0 6.0 5.0 4.0 3.0 r=-0.546 P<0.0001 2.0 130.0 145.0 160.0 175.0 190.0 Body height (cm) London GM personal data
First minimum of impedance (Hz) Relationship between the first minimum of impedance modulus and aortic PWV 9.0 8.0 7.0 6.0 5.0 4.0 3.0 r=0.495 P<0.0001 London GM personal data 2.0 600.0 900.0 1200.0 1500.0 1800.0 Aortic PWV (cm/s)
Schematic representation of vascular impedance (Modulus= Pressure/flow) 2000 Zr=Zr Control ESRD Modulus (dynes sec cm-5) 1500 1000 500 f min f min Zc Zc 0 0 1 2 3 4 5 6 7 (Heart rate) Frequency (Hertz)
Representation of the impedance modulus and amplitude (power) of flow harmonics Modulus (dynes sec cm-5) 1500 1000 500 First minimum of impedance modulus Flow (ml/m) for different frequencies 0 0 1 2 3 4 5 6 7 Cycles (multiples of 1st in Hertz) (1st = Heart rate)
Impedance modulus and flow harmonics during exercise (shift of flow harmonics with increased heart frequency) Modulus (dynes sec cm-5) 1500 1000 500 Flow (ml/m) 0 (Heart rate) 0 1 2 3 4 5 6 7 Cycles (Hertz)
Heart rate - 200 (3.3Hz) 1st minimum of impedance is close to heart rate (i.e. frequency of the highest flow harmonic for lowest pressure harmonic) Heart rate 60 (1Hz) heart rate is far from 1st min. of impedance (flow develops a high pressure)
First minimum of impedance (Hz) Relationship between the first minimum of impedance modulus and heart period 7.0 6.0 R=-0.240 p=0.003 5.0 4.0 3.0 2.0 600 1.66 Hz London GM personal data 800 1.25 Hz 1000 1 Hz 1200 0.83 Hz Heart Period (ms) 1400 0.71 Hz
Fmin/Heart frequency (ratio) Relationship between the ratio of the first minimum of impedance modulus and heart period and body height (better coupling between heart rate and arterial properties in tall subjects 7.0 6.0 R=-0.280 P<0.0001 5.0 4.0 3.0 London GM personal data 2.0 130.0 145.0 160.0 175.0 190.0 Body Height (cm)
LV velocity of fiber shortening (c/s) Correlation between Fmin/heart frequency and Left Ventricular velocity of fiber shortening 2.0 1.7 r=-0.338 P<0.001 1.4 1.2 0.9 London GM personal data 0.6 2.0 4.0 6.0 8.0 10.0 Fmin/heart frequency (ratio)
Reflected Wave SPTI DPTI SPTI DPTI
CBF (ml/min) BP (mmhg) Superimposed simultaneous phasic recording of aortic (Ao), left ventricular (LV) pressures and coronary blood flow (CBF) (Buckeberg et al. Circ Res. 1972) 100 Ao Ao DPTI DPTI 0 STTI LV STTI LA or PA Wedge 100
LV endo:epi flow ratio DPTI/SPTI plotted against Left Ventricular flow distribution between endocardium and epicardium 1.2 1.0 0.8 0.6 0.4 0.2 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 DPTI/SPTI Adapted from Buckberg et al 1972
Correlation between left ventricular mass and aortic pulse wave velocity 200 Left ventricular mass (g/m 2 ) 150 100 r = 0.52 p < 0.001 London et al KI 1989 500 1000 1500 2000 Aortic pulse wave velocity (cm/sec)
Survival Aortic stiffness and all-cause mortality in general population (Laurent et al Hypertension 2001) Kaplan-Meier P<0.0001 1.00 Low PWV tertile 0.90 Medium PWV tertile 0.80 High PWV tertile 0.70 0 5 10 15 20 Follow-up (years)
Cardiovascumar survival Wave reflection (Aix) and cardiovascular survival Log rank test for cardiovascular mortality. Chi square =23.11 ; P<0.0001. 1 AIX : 1 st quartile 0.75 AIX : 2 nd quartile AIX : 3 rd quartile 0.50 AIX : 4 th quartile 0.25 0 0 35 70 105 140 Duration of follow-up (months) London et al Hypertension 2001
Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by Age ISH (SBP ³140 mm Hg and DBP <90 mm Hg) SDH (SBP ³140 mm Hg and DBP ³90 mm Hg) IDH (SBP <140 mm Hg and DBP ³90 mm Hg) 100 17% 16% 16% 20% 20% 11% Frequency of hypertension subtypes in all untreated hypertensives (%) 80 60 40 20 0 <40 40-49 50-59 60-69 70-79 80+ Age (y) Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874.
Evolution of Untreated Systolic and Diastolic BP: The Framingham Heart Study n=2036 160 140-159 120-139 <120 Adapted from Franklin et al. Circulation 1997;96:308.
2-year risk of endpoint Cardiovascular Risk Associated with Increasing SBP at Fixed Values of DBP 0.28 0.24 0.20 0.16 EWPHE (n = 840) SYST-EUR (n = 4695) SYST-CHINA (n = 2394) 75 80 85 90 95 DBP (mm Hg) 0.12 0.08 0.04 120 140 160 180 200 SBP (mm Hg) 220 240 Two-year risk adjusted for active treatment, sex, age, previous CV complications, and smoking by multiple Cox regression. Staessen, et al. Lancet. 2000;355:865 872.
Pulse Pressure (mm Hg) Pulse Pressure (mm Hg) Pulse Pressure (mm Hg) Correlation between arterial pulse pressure, wave reflexion (Augmentation index) aortic pulse wave velocity and stroke volume (n=230) 160 160 132 R=0.47 p<0.0001 132 R=0.60 p<0.0001 104 104 76 76 48 48 20-40 -15 10 35 60 Augmentation Index (%) 160 20 500 1000 1500 2000 2500 Aortic pulse wave velocity (cm/s) 132 R=0.15 p=0.035 104 76 48 dapted from London et al KI 1996 20 20 55 90 125 160 stroke volume (ml)
Pulse wave analysis:
Definition of waveform landmarks, AI, and characteristic impedance Mitchell, G. F. et al. Hypertension 2001;38:1433-1439
Arterial Pressure Waves Recorded in Young Subjects Normotensiv e Subjects Pseudo- Hypertensio n Essential Hypertensio n Mahmud A, Feely J. American J Hypertens 2003;16:229-232
M O Rourke, Eur Heart J, 1990
BRACHIAL BLOOD PRESSURES at 1 year 0-5 -10-23.1-16.2-13.3-12.9-16.6-14.0-9.9-3.3-15 -20-25 p<0.001 NS p=0.019 p<0.001 SBP DBP MBP PP Per/Ind (n=204) atenolol (n=202) Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
AORTIC SBP ( At 1 year) 0-4 p<0.001-22.5 p<0.001-8.0 SBP (mmhg) -8-12 -16-20 -24 p<0.001 Per/Ind (n=65) Aténolol (n=65) Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
AORTIC PP (At 1 year) p<0.001* 2 2.3 PP (mmhg) -2-9.3 NS -6-10 p<0.001 Per/Ind Aténolol (n=65) (n=65) Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
PWV (carotido-femoral) PWV (m/s) 0-0,5 p<0.001 p<0.001-0.79-0.99-1 -1,5-2 Per/Ind NS* atenolol Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
AUGMENTATION INDEX (aortic) p<0.001* 2 1 1.83 AIX (%) 0-1 -2-3.06 NS -3-4 p=0.002 Per/Ind atenolol * Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
LEFT VENTRICULAR HYPERTROPHY LVH (g/m2) 0 p=0.031-3 -5.3-6 -9-11.3-12 Per/Ind p<0.001 Aténolol p=0.012 Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7
Arterial Impedance Gradients Zc-characteristic impedance; Zr-peripheral resistance ( ) ReflectionCoefficient = Zr -Zc - Zr - + Zc Zc P b P f Z R P t PWV=6 m/s PWV=10 m/s Pb P f P t PWV=12 m/s PWV=11 m/s Aorta Muscular arteries Resistance vessels