Pharmacological modulation of vascular structure and function. L. Van Bortel. Heymans Institute of Pharmacology, Ghent University

Transcription

1 Pharmacological modulation of vascular structure and function L. Van Bortel Heymans Institute of Pharmacology, Ghent University BHC 2015

2 Pharmacological modulation of Endothelial function CIMT Pulse wave reflection/central blood pressure Arterial stiffness

3 Pharmacological modulation of endothelial function ACEI + nonvd BB = ARB + VD BB* +/= Aldost antag + CCB* =/+ Diuretics = statins + PDE5 inhibitors + *Macrocirculation/microcirculation Masoura C et al. Atherosclerosis 2011; 214: Ghiadoni L et al. Curr Vascul Pharmacol 2012; 10: Shahin Y et al. Atherosclerosis 2011: 216; Vanhoutte P et al. Curr Opinion Pharmacol 2013;13: Zhang L et al. Atherosclerosis 2012; 223: Schwartz et al. Am J Med 2013; 126:192-9 Vlachopoulos et al. Atherosclerosis 2015; 241:507-32

4 Prognostic value of EF 1% in FMD 8 13% in cardiovascular risk Added value to classical risk scores: not established Few studies with conflicting results Reference values: no Vlachopoulos et al. Atherosclerosis 2015; 241:507-32

5 Pharmacological modulation of Endothelial function CIMT Pulse wave reflection Arterial stiffness

6 Pharmacological modulation of CIMT Effect is slow (months-years) Drug class effect reference β-blockers Wang, Cuspidi α-blockers Wang Diuretics Cuspidi statins /= Masoura, Huang Vlachopoulos et al. Atherosclerosis 2015; 241:507-32

7 Pharmacological modulation of CIMT Drug class effect reference ACE-inhibitors Wang, Cuspidi Angiotensin receptor blockers Wang Direct Renin Inhibitors Nakamura Aldosterone antagonists Vukusich Calcium channel blockers Wang, Cuspidi

8 Vasodilation decreases CIMT Difference (IMT dia IMT sys ) = 25 µ (3.8%) Van Bortel. J Hypertens 2005; 23:37-39 IMT or IMarea? IMarea can distinguish between a vasodilation-induced functional decrease in IMT a real structural decrease in IMT

9 Is increased Carotid IMT marker or early stage of atherosclerosis?

10 Contra early stage IMT increases 1. Increased tensile stress (cfr atletes) Mayet et al. J cardiovasc Risk 2002; 9: Low shear Kornet et al Atvb 1998; 18: Age 4. After radiotherapy of neck Dorresteijn et al. Eur J Cancer 2005; 41:

11 Pro early stage 1. Associations described with numerous cardiovascular risk factors Mackinnon et al. Stroke 2004; 35: Good correlation with Framingham Risk score Touboul et al. Stroke 2005; 36: IMT number of plaques. Rosvall et al. Atherosclerosis 2005; 179:

12 % of plaques according to IMT tertiles Rosvall et al. J Int Med 2005; 257:

13 Pro early stage 1.Associations described with numerous cardiovascular risk factors Mackinnon et al. Stroke 2004; 35: Good correlation with Framingham Risk score Touboul et al. Stroke 2005; 36: IMT number of plaques. Rosvall et al. Atherosclerosis 2005; 179: High IMT independent predictor of stroke

14 Stroke hazard ratios for IMT tertiles Rosvall et al. Atherosclerosis 2005; 179:

15 Meaning of Carotid IMT Beyond a certain level IMT represents more likely atherosclerosis (The Rotterdam Study) Bots et al. Stroke 1997; 28: Cutoff: 900 µ ESH guidelines. J Hypertens 2003; 21:

16 Pro early stage 1.Associations described with numerous cardiovascular risk factors Mackinnon et al. Stroke 2004; 35: Good correlation with Framingham Risk score Touboul et al. Stroke 2005; 36: IMT number of plaques. Rosvall et al. Atherosclerosis 2005; 179: High IMT independent predictor of stroke 5.Prognostic value: 0.1 mm in IMT 16% risk for future CV events in general population (meta-analysis 16 studies, n=36984) Lorenz et al. Lancet 2012;379:

17 Normal values of IMT measured with echo-tracking males Engelen et al. Eur Heart J 2013; 34:

18 Normal values of IMT measured with echo-tracking males Engelen et al. Eur Heart J 2013; 34:

19 Added predictive value of carotid IMT No added predictive value versus FRS Den Ruyter et al. JAMA 2012;308: carotid plaques improve risk prediction of coronary events Meta-analysis (n=54336) Inaba et al. Atherosclerosis 2012;220: predicted CV mortality independently of SCORE Sehestedt et al. Eur Heart J 2010;31:883-91

20 Pharmacological modulation of Endothelial function CIMT Pulse wave reflection Arterial stiffness

21 Vascular determinants of pulse wave reflection Pulse wave velocity (stiffness) Distance of major reflection points to the heart Changes in impedance (~ contractile status)

22 Pharmacological modulation of central AIx ACEI Aldosterone antagonists ARB Other diuretics = DRI nonvd BB CCB VD BB =/ Nitrates PDE5 inhibitors Boutouyrie P et al. Drugs 2011; 71: Virdis et al. Eur Heart J 2012; 33: Vlachopoulos et al. J Clin Pharmacol 2012; 52: O Rourke and Hashimoto. J Cardiopulm Rehabil Prev 2008; 28: Dhakam et al. J Hypertens 2008; 26: 351-6

23 AIx is NOT a surrogate for arterial stiffness Effect of Age on AIx, AP and PWVao McEniery et al. JACC 2005; 46:

24 AIx is NOT a surrogate for arterial stiffness Effect of isoprenaline on cfpwv and central AIx and PP placebo isoproterenol Δ Pvalue cfpwv (m/s) 6.07± ± cpp (mmhg) 33±5 37± AIx(%) 6.3± ± < Lemogoum et al. J Hypertens 2004; 22: Determinants of AIx (Asklepios study) n=2524 determinant Pearson correlation PWV 0.28 Age 0.35 TPR 0.42

25 methods for wave reflection Reflection magnitude versus AIx and PPA Risk for cardiovascular events in MESA study hemodynamic measure HR (95% CI) P augmentation index 1.07 (0.98, 1.19) 0.19 pulse pressure amplification 0.99 (0.89, 1.10) 0.78 reflection magnitude 1.17 (1.05, 1.30) Chirinos et al. J Am Coll Cardiol 2012; 60: AIx is poor surrogate for wave reflection Reflection magnitude is better surrogate for wave reflection BHC 2015

26 Pharmacological modulation of central BP drug effect csbp beyond psbp studies (n) + neutral - range diuretics / +0.3 BB 8-10 / -1.5 CCB (DHP) / +2.7 ACEI / +10 ARB / +6.5 DRI 1 nitrates 3 +4 / PDE5 inhibitors trend Protogerou et al. Curr Pharmaceut Design 2009; 15: Schneider et al. J Ren Ang Aldost syst 2008; MacKenzie et al. Hypertension 2009; 54: Virdis et al. Eur Heart J 2012; 33: Vlachopoulos et al. J Clin Pharmacol 2012; 52:

27 Lower Heart Rate increases AIx and csbp O atenolol Δ nebivolol placebo Dhakam et al. J Hypertens 2008; 26: 351-6

28 Normal values of csbp Herbert A et al. Eur Heart J 2014; 35:

29 Prognostic value of wave reflection Augmentation index 10% increase in AIx total CV events RR 1.32 All cause mortality RR 1.38 Vlachopoulos et al. Eur Heart J 2010; 31: Independent predictor of CV events But PV AIx < cfpwv Added value to risk scores??? Not tested BHC 2015

30 Predictors of a major CV event The Framingham Heart Study hemodynamic measure HR (95% CI) P carotid-femoral (aortic) PWV 1.48 (1.16, 1.91) carotid-radial 1.07 (0.92, 1.25) 0.77 (muscular artery) PWV augmentation index 0.91 (0.77, 1.07) 0.24 central pulse pressure 1.00 (0.99, 1.01) 0.98 pulse pressure amplification 0.86 (0.19, 3.82) 0.84 G. Mitchell et al. Circulation 2010; 121: BHC 2015

31 Effect of antihypertensive drugs on Endothelial function CIMT Pulse wave reflection Arterial stiffness

32 Effect of antihypertensive drugs on arterial stiffness decrease ACEI ARBs DRI CCB selective β1 blockers β1 blockers + VD nitrates some diuretics increase nonselective β blockers clonidine direct vasodilators urapidil some diuretics Van Bortel L et al. J Hum Hypertens 1998; 12: Asmar R et al. J Ren Ang Ald Syst 2002; 3: Expert consensus document. Eur Heart J 2006; 27: Virdis A. et al. Eur Heart J :1530-8

33 Effect of Perindopril and amiloride/hydrochlorothiazide after 3 and 6 months treatment Kool et al. J Hypertens 1995; 13:

34 Change in PWV in trials <1 month Adjusted for MBP, HR, gender, CV risk factors Ong et al. J Hypertens 2011; 29:

35 Studies 1-12 months: not all studes included Shahin et al. Atherosclerosis 2012; 221:18-33

36 Change in PWV in trials > 1 month Adjusted for MBP, HR, gender, CV risk factors long term BP per se may improve PWV Ong et al. J Hypertens 2011; 29:

37 Effect of olmesartan on cfpwv Laurent et al. Hypertension 2014;64:709-16

38 Relative risk of 1 m/s increase in aortic PWV Meta-analysis of 13 longitudinal studies event RR (95%CI) P n total cardiovascular events 1.14 (1.09, 1.20) < cardiovascular mortality 1.15 (1.09, 1.21) < all-cause mortality 1.15 (1.09, 1.21) < C. Vlachopoulos et al. JACC 2010; 55:

39 Aortic PWV has added value Primary CHD risk within 6 yrs in hypertensives Tertiles of Framingham score Tertiles of pulse wave velocity Boutouyrie P et al. Hypertension 2002

40 Aortic PWV is gold standard Added value: reclassify to higher or lower risk Boutouyrie P. et al. Hypertension 2002;39: Sehestedt T et al. Eur Heart J 2010;31: Sehestedt T et al. J Hypertens 2012;30:

41 Aortic PWV is gold standard Added value: reclassify to higher or lower risk Boutouyrie P. et al. Hypertension 2002;39: Sehestedt T et al. Eur Heart J 2010;31: Sehestedt T et al. J Hypertens 2012;30:

42 TAPE estimated distance (CA-FA) (SSN-CA) (CA-FA) (SN-CA) (SSN-FA) (SSN-CA) (CA-FA) (SN-FA) (SN-CA) (CA-FA) x 0.8 Body height/ Body height x 0.29 Multiple distances make impossible Comparison of different methods Pooling of data Use of a fixed cutoff value current cutoff value 12 m/s Only applicable to direct (CA-FA) full distance method Huybrechts et al. J Hypertens 2011; 29:

43 TAPE estimated APL Tape - MRI Mean (SD) Huybrechts et al. J Hypertens 2011; 29: Tape/MRI % Cutoff m/s (CA-FA) (SSN-CA) 2.32 (3.8) +4% 9.98 (CA-FA) (SN-CA) (3.8) -5% 9.12 (SSN-FA) (SSN-CA) (3.5) - 10% 8.64 (CA-FA) (4.2) +25% (SN-FA) (SN-CA) (3.9) -29% 6.82 (CA-FA) x (3.8) +0.4% 9.64 Body height/ (3.9) -1% 9.50 Body height x (4.0) -1.8% 9.43

44 TAPE estimated APL Tape - MRI Mean (SD) Huybrechts et al. J Hypertens 2011; 29: Tape/MRI % Cutoff m/s (CA-FA) (SSN-CA) 2.32 (3.8) +4% 9.98 (CA-FA) (SN-CA) (3.8) -5% 9.12 (SSN-FA) (SSN-CA) (3.5) - 10% 8.64 (CA-FA) (4.2) +25% (SN-FA) (SN-CA) (3.9) -29% 6.82 (CA-FA) x (3.8) +0.4% 9.64 Body height/ (3.9) -1% 9.50 Body height x (4.0) -1.8% 9.43

45 How to convert measured PWV-values to standard values? Use Table 1 of consensus document on measurement of cf-pwv or conversion formula J Hypertens 2012; 30:445-8 e.g. measured PWV: 9.5 m/s Standard PWV = measured PWV*distance[(CA-FA)x0.8]/distance[used method] Standard PWV = 9.5*50.9/45.5 = m/s (Sphygmocor) Standard PWV = 9.5*50.9/63.6 = 7.60 m/s (Complior) Standardisation needed

46 Reference values of aortic PWV Based on 80% of direct distance The reference values for arterial stiffness collaboration. Eur Heart J 2010; 31:

47 Aim To create an application for easy assessment of standard carotid-femoral PWV local arterial stiffness for different methodological approaches providing the percentile reference value Application available online at:

48 cf-pwv Reference Values * Reference Values for Arterial Stiffness Collaboration database (24484 subjects) Normal Values Population (1455 subjects) Derived equations * The Reference Values for Arterial Stiffness Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: establishing normal and reference values. European Heart Journal (2010) 31,

49 Carotid DC Reference Values * Total Carotid Stiffness population (23007 subjects) Men Healthy sub-population (3601 subjects) Women Four Derived equations Expected mean of carotid DC and expected standard deviation of carotid DC for men and for women * Reference values for local arterial stiffness. Part A: Carotid artery. Engelen L, Bossuyt J, Ferreira I, Van Bortel L, Reesink KD, Segers P, Stehouwer CD, Laurent S, Boutouyrie P. Journal of Hypertension (2015) 33,

50 Femoral DC Reference Values * Total Femoral Stiffness population (5069 subjects) Men Healthy sub-population (1489 subjects) Women Four Derived equations Expected mean of femoral DC and expected standard deviation of femoral DC for men and for women * Reference values for local arterial stiffness. Part B: Femoral artery. Bossuyt J,Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Laurent S, Segers P, Reesink KD, Van Bortel L. Journal of Hypertension (2015) 33,

51 The Application

52 0-1 cm 1 cm 1-2 cm 2 cm ART.LAB Wall Track System Vivid-7 Carotid Studio Application available online at:

53 DC Stiffness Percentile Stiffness Application available online at:

54 (CA-FA) (SSN-CA) (CA-FA) (SN-CA) (SSN-FA) (SSN-CA) (CA-FA) (SN-FA) (SN-CA) (CA-FA) x 0.8 Body height/ Body height x 0.29 Application available online at:

55 PWV Stiffness Percentile Stiffness Application available online at:

56 (CA-FA) (SSN-CA) (CA-FA) (SN-CA) (SSN-FA) (SSN-CA) (CA-FA) (SN-FA) (SN-CA) (CA-FA) x 0.8 Body height/ Body height x 0.29 Application available online at:

57 PWV Stiffness Percentile Stiffness Application available online at:

58 Conclusions We developed a tool that Is easy to use also on mobile phone! Assess a given measurement of Arterial Stiffness from a subject and delivers its percentile in reference to a Healthy population Is available at

59 Perspective Give your comments to improve the application so that Arterial Stiffness becomes a routine parameter for clinical use Application available online at:

60 Summary (1) Endothelial function Vasodilating drugs improve EF ACEI>macrocirculation CCB>microcirculation Nonvasodilating BB and diuretics: neutral CIMT All firstline antihypertensive drugs decrease CIMT effect of drug or BP Larger decrease in CIMT with CCBs due to larger vasodilation? Vasodilating drugs: assess IMarea instead of IMT Wave reflection Vasodilating drugs early wave reflection and csbp Diuretics: neutral Non VD BB: due to lower heart rate BHC 2015

61 Summary (2) Arterial stiffness All first line antihypertensive drugs improve arterial stiffness on the long term, suggesting that BP per se may be beneficial ACEIs and ARBs appear to have a larger effect beyond BP suggesting direct effect The clinical relevance of this larger effect is currently hard to estimate because of methodological issues Therefore investigators should be urged to deny user manuals of the devices and to use the standard method to measure cfpwv or to convert the results to the standard method