Effects of Renin-Angiotensin System blockade on arterial stiffness and function. Gérard M. LONDON Manhès Hospital Paris, France

Transcription

1 Effects of Renin-Angiotensin System blockade on arterial stiffness and function Gérard M. LONDON Manhès Hospital Paris, France

2 Determinants of vascular overload (afterload) on the heart Peripheral Resistance Arterial Stiffness Wave reflection Inertance

3 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

4 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

5 The arterial wall is a heterogeneous material Distensible balloon (rubber=elastin) Rigid/stiff net (steel=collagen) A.Tedgui and B. Levy, 1994

6 The arterial wall is a heterogeneous material A.Tedgui and B. Levy, 1994

7 Pressure Diagrammatic representation of pressure-volume relationships Einc=2 Einc=1 dp/dv Volume

8 Blood pressure Blood pressure Arterial function and blood pressure Pure Conduit Function Conduit and Cushioning Function Mean pressure Mean pressure Systole Diastole Systole Diastole

9 Aortic PWV (cm/s) Correlation between common carotid artery (CCA) distensibility and aortic pulse wave velocity (PWV)in human population r= p< CCA distensibility (kpa )

10 Pressure wave analysis measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity

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12 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

13 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) R= p< aortic PWV (cm/s)

14 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 R=0.585 p< Body height (cm)

15 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

16 Survival Aortic stiffness and all-cause mortality in general population (Laurent et al Hypertension 2001) Kaplan-Meier P< Low PWV tertile 0.90 Medium PWV tertile 0.80 High PWV tertile Follow-up (years)

17 Cardiovascumar survival Wave reflection (Aix) and cardiovascular survival Log rank test for cardiovascular mortality. Chi square =23.11 ; P< AIX : 1 st quartile 0.75 AIX : 2 nd quartile AIX : 3 rd quartile 0.50 AIX : 4 th quartile Duration of follow-up (months) London et al Hypertension 2001

18 (mm Hg) (mm Hg) (mm Hg) Pressure Waves Recorded Along the Arterial Tree Maximum Early Wave Reflection Age 68 years Age 54 years Maximum Amplification Renal artery Age 24 years Femoral artery Thoracic aorta Abdominal aorta Iliac artery Ascending aorta Nichols WW, et al. Arterial Vasodilation. Philadelphia,1993;32.

19 Arterial Pressure Waves Recorded in Young Subjects Normotensive Subjects Pseudo- Hypertension Essential Hypertension Mahmud A, Feely J. American J Hypertens 2003;16:

20 M O Rourke, Eur Heart J, 1990

21 C.H.Chen et al.,hypertension, 1995

22 AUC: p=0.001 vs baseline, vs atenolol Cross-over: 3x 4 weeks, n=20 B Pannier et al., Clin Exp Pharmacol Physiol, 2001

23 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:

24 BRACHIAL BLOOD PRESSURES at 1 year 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

25 AORTIC SBP ( At 1 year) 0-4 p< p< SBP (mmhg) p<0.001 Per/Ind (n=65) Aténolol (n=65) Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7

26 AORTIC PP (At 1 year) p<0.001* PP (mmhg) NS p<0.001 Per/Ind Aténolol (n=65) (n=65) Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7

27 PWV (carotido-femoral) PWV (m/s) 0-0,5 p<0.001 p< ,5-2 Per/Ind NS* atenolol Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7

28 AUGMENTATION INDEX (aortic) p<0.001* AIX (%) NS -3-4 p=0.002 Per/Ind atenolol * Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7

29 LEFT VENTRICULAR HYPERTROPHY LVH (g/m2) 0 p= Per/Ind p<0.001 Aténolol p=0.012 Asmar R, London G, O Rourke M et al. Hypertension 2001;38 : 922-7

30 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

31 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

32 Survival rate All cause survival according to changes in aortic pulse wave velocity ( PWV) in response to BP decrease Decreased PWV = P< Increased or unchangedpwv Duration of follow-up (months) Guérin et al. Circulation

33 Aortic PWV (m/s) Aortic PWV (m/s) Aortic PWV (m/s) Mean blood pressure (mm Hg) ACEi - Ca Mean blood pressure (mm Hg)

34 Survivorship Probability of all-cause survival according to prescription (alone or in combination) of perindopril (+ yes ; - no). ²=23.3; p< Perindopril Perindopril Time (months) From Guérin et al. Circulation 2001

35 Serum CRP (LN mg/l) Serum CRP levels in ESRD patients with treatment including or not ACE inhibitor (Perindopril) 3.5 P= London et al Kidney Int 2003 Without Perindopril ( ) With Perindopril ( )

36 mm Hg The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Peripheral And Central Pulse Pressure (PP) on Amlodipine/Perindopril and Atenolol-based Therapy Brachial PP Diff Mean (AUC) = -0.9 (-1.9, 0) mm Hg Atenolol Amlodipine/perindopril P= Central PP Diff Mean (AUC) = 3 (2.1, 3.9) mm Hg The CAFE investigators; Circulation 2005 in press Time (Years) 43.4 P<.0001 AUC

37 mm Hg The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Peripheral And Central SBP on Amlodipine/perindopril and Atenolol-based Therapy Brachial SBP Diff Mean (AUC) = 0.7 (-0.4,1.7) mm Hg SBP Atenolol Amlodipine/perind P= Central SBP Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg Time (Years) P<.0001 AUC The CAFE investigators; Circulation 2005 in press

38 Cumulative Incidence (%) The Conduit Artery Functional Evaluation (CAFE) Study in ASCOT Total CV Events and Procedures + Development of Renal Impairment Atenolol Amlodipine HR=0.84 ( ) P< Number at risk Years Amlodipine Atenolol The CAFE investigators; Circulation 2005 in press