Effects of Renin-Angiotensin System blockade on arterial stiffness and function Gérard M. LONDON Manhès Hospital Paris, France
Determinants of vascular overload (afterload) on the heart Peripheral Resistance Arterial Stiffness Wave reflection Inertance
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
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
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 )
Pressure wave analysis measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity
Aortic arterial pressure waveforme P= augmented pressure P PP=pulse pressure Augmentation index= P/ PP Tsh= time to shoulder PP LVET=left ventricular ejection time Tsh LVET
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)
Influence of Left ventricular ejection time (heart rate) on the timing of forward and reflected Waves and on Systolic Augmentation Pressure (Aix) Positive Aix Negative Aix. T T LVET LVET Forward-traveling wave Backward-traveling reflected wave Actual (composite) wave T - traveling time of pressure wave to reflecting sites and back
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
(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.
Arterial Pressure Waves Recorded in Young Subjects Normotensive Subjects Pseudo- Hypertension Essential Hypertension Mahmud A, Feely J. American J Hypertens 2003;16:229-232
M O Rourke, Eur Heart J, 1990
C.H.Chen et al.,hypertension, 1995
AUC: p=0.001 vs baseline, vs atenolol Cross-over: 3x 4 weeks, n=20 B Pannier et al., Clin Exp Pharmacol Physiol, 2001
Mean values and SEM in group 1 (no baseline AII inhibition) for aortic systolic blood pressure and augmentation index in relation to ingestion at 8:00 AM on different study days of placebo, 600 mg eprosartan, 25 mg captopril, and 60 mg ISMN Stokes, G. S. et al. Hypertension 2003;41:297-301
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
Left ventricular mass index (g/m²) Comparative effect of perindopril and nitrendipine on left ventricular mass index (g/m²) nitrendipine 200 perindopril * p<0.01 vs base p<0.01 vs nitrendipine 150 * * inclusion 6 months 12 months London et al Circulation 1994
Approach to reduction of blood presure and aortic stiffness with antihypertensive treatment Control of overhydration BP>160/90 perindopril nitrendipine BP>160/90 Perindopril + atenolol Nitrendipine + atenolol BP>160/90 Perindopril-atenolol-nitrendipine Nitrendipine-atenolol-perindopril Guérin et al Circulation 2001
Survival rate All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease 1 0.75 0.50 Decreased PWV 0.25 2 = 28.01 P<0.00001 0 Increased or unchangedpwv 0 35 70 105 140 Duration of follow-up (months) Guérin et al. Circulation. 2001.
Aortic PWV (m/s) Aortic PWV (m/s) Aortic PWV (m/s) 8 6 4 2 0-2 -4-6 8 6 4 2 0-2 -4-6 -8-8 -80.0-60.0-40.0-20.0 0.0 20.0 40.0-80.0-60.0-40.0-20.0 0.0 20.0 40.0 Mean blood pressure (mm Hg) 8 6 4 ACEi - Ca- 2 0-2 -4-6 -8-80.0-60.0-40.0-20.0 0.0 20.0 40.0 Mean blood pressure (mm Hg)
Survivorship Probability of all-cause survival according to prescription (alone or in combination) of perindopril (+ yes ; - no). ²=23.3; p<0.0001 1.00 0.75 Perindopril + 0.50 0.25 Perindopril - 0.00 0.0 35 70 105 140 Time (months) From Guérin et al. Circulation 2001
Serum CRP (LN mg/l) Serum CRP levels in ESRD patients with treatment including or not ACE inhibitor (Perindopril) 3.5 P=0.009 3 2.5 2 1.5 1 0.5 0 London et al Kidney Int 2003 Without Perindopril (11.8 11.1) With Perindopril (7.3 9.7)
mm Hg The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Peripheral And Central Pulse Pressure (PP) on Amlodipine/Perindopril and Atenolol-based Therapy 58 53 Brachial PP Diff Mean (AUC) = -0.9 (-1.9, 0) mm Hg Atenolol Amlodipine/perindopril 56.2 55.3 P=.06 45 46.4 43 Central PP Diff Mean (AUC) = 3 (2.1, 3.9) mm Hg 38 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 The CAFE investigators; Circulation 2005 in press Time (Years) 43.4 P<.0001 AUC
mm Hg The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Peripheral And Central SBP on Amlodipine/perindopril and Atenolol-based Therapy 140 135 130 Brachial SBP Diff Mean (AUC) = 0.7 (-0.4,1.7) mm Hg SBP Atenolol Amlodipine/perind. 133.9 133.2 P=.07 125 125.5 120 115 Central SBP Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Time (Years) 121.2 P<.0001 AUC The CAFE investigators; Circulation 2005 in press
Cumulative Incidence (%) The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Total CV Events and Procedures + Development of Renal Impairment 25.0 20.0 15.0 Atenolol Amlodipine 10.0 5.0 0.0 HR=0.84 (0.79-0.90) P<.0001 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Years Amlodipine 9639 9166 8808 8455 8118 6965 Atenolol 9618 9115 8692 8259 7872 6710 The CAFE investigators; Circulation 2005 in press