Abstract
Arterial stiffness has emerged as an important marker of cardiovascular risk in various populations and reflects the cumulative effect of cardiovascular risk factors on large arteries, which in turn is modulated by genetic background. Arterial stiffness is determined by the composition of the arterial wall and the arrangement of these components, and can be studied in humans non-invasively. Age and distending pressure are two major factors influencing large artery stiffness. Change in arterial stiffness with drugs is an important endpoint in clinical trials, although evidence for arterial stiffness as a therapeutic target still needs to be confirmed. Drugs that independently affect arterial stiffness include antihypertensive drugs, mostly blockers of the renin-angiotensin-aldosterone system, hormone replacement therapy and some antidiabetic drugs such as glitazones. While the quest continues for ‘de-stiffening drugs’, so far only advanced glycation endproduct cross-link breakers have shown promise.
Similar content being viewed by others
References
Protogerou AD, Papaioannou TG, Lekakis JP, et al. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part I: (patho)-physiology, rationale and perspective on pulse pressure amplification. Curr Pharm Des 2009; 15(3): 267–71
Protogerou AD, Stergiou GS, Vlachopoulos C, et al. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part II: evidence for specific class-effects of antihypertensive drugs on pressure amplification. Curr Pharm Des 2009; 15(3): 272–89
Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries. 3rd ed. London: Lippincott, Williams and Wilkins, 1990
Boutouyrie P, Briet M, Collin C, et al. Assessment of pulse wave velocity. Artery Reseach 2009; 3(1): 3–8
Laurent S, Cockcroft J, Van Bortel L, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27(21): 2588–605
Bramwell LC, Hill AV.Velocity of transmission of the pulse wave. Lancet 1922; I: 891–2
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’. Eur Heart J 2010; 31(19): 2338–50
Hoeks AP, Brands PJ, Smeets FA, et al. Assessment of the distensibility of superficial arteries. Ultrasound Med Biol 1990; 16(2): 121–8
Hoeks AP, Willekes C, Boutouyrie P, et al. Automated detection of local artery wall thickness based on M-line signal processing. Ultrasound Med Biol 1997; 23(7): 1017–23
Zulliger MA, Fridez P, Hayashi K, et al. A strain energy function for arteries accounting for wall composition and structure. J Biomech 2004; 37(7): 989–1000
Boutouyrie P, Bussy C, Lacolley P, et al. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation 1999; 100(13): 1387–93
Benetos A, Laurent S, Boutouyrie P, et al. Alteration in the carotid artery wall properties with ageing and high blood pressure level. J Hypertens Suppl 1991; 9(6): S112–3
Boutouyrie P, Laurent S, Benetos A, et al. Opposing effects of ageing on distal and proximal large arteries in hypertensives. J Hypertens Suppl 1992; 10(6): S87–91
Parlakian A, Charvet C, Escoubet B, et al. Temporally controlled onset of dilated cardiomyopathy through disruption of the SRF gene in adult heart. Circulation 2005; 112(19): 2930–9
Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats: effects of eplerenone. Circulation 2002; 106(22): 2848–53
Kakou A, Bezie Y, Mercier N, et al. Selective reduction of central pulse pressure under angiotensin blockage in SHR: role of the fibronectin-alpha5beta1 integrin complex. Am J Hypertens 2009; 22(7): 711–7
Lacolley P, Safar ME, Regnault V, et al. Angiotensin II, mechanotransduction, and pulsatile arterial hemodynamics in hypertension. Am J Physiol Heart Circ Physiol 2009; 297(5): H1567–75
Labat C, Lacolley P, Lajemi M, et al. Effects of valsartan on mechanical properties of the carotid artery in spontaneously hypertensive rats under high-salt diet. Hypertension 2001; 38(3): 439–43
Albaladejo P, Bouaziz H, Duriez M, et al. Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats. Hypertension 1994; 23(1): 74–82
Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol 2010; 6(5): 261–73
Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension 2005; 45(6): 1050–5
Mahmud A. Reducing arterial stiffness and wave reflection: quest for the holy grail. Artery Res 2007; 1: 13–9
McEniery CM, Yasmin, Hall IR, et al. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005; 46(9): 1753–60
Pannier BM, Kando T, Safarian AA, et al. Altered hemodynamic response to isosorbide dinitrate in essential hypertension. J Clin Pharmacol 1990; 30: 127–32
Laurent S, Arcaro G, Benetos A, et al. Mechanism of nitrate-induced improvement on arterial compliance depends on vascular territory. J Cardiovasc Pharmacol 1992; 19: 641–9
Kool MJ, Spek JJ, Struyker Boudier HA, et al. Acute and subacute effects of nicorandil and isosorbide dinitrate on vessel wall properties of large arteries and hemodynamics in healthy volunteers. Cardiovasc Drugs Ther 1995; 9: 331–7
Starmans-Kool MJ, Kleinjans HA, Lustermans FA, et al. Treatment of elderly patients with isolated systolic hypertension with isosorbide dinitrate in an asymmetric dosing schedule. J Hum Hypertens 1998; 12: 557–61
Mitchell GF, Izzo Jr JL, Lacourcière Y, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation 2002; 105: 2955–61
Ong KT, Delerme S, Pannier B, et al. Aortic stiffness is reduced beyond blood pressure lowering by short-term and long-term antihypertensive treatment: a meta-analysis of individual data in 294 patients. J Hypertens 2011; 29(6): 1034–42
Ait-Oufella H, Collin C, Bozec E, et al. Long-term reduction in aortic stiffness: a 5.3-year follow-up in routine clinical practice. J Hypertens 2010; 28(11): 2336–41
Tropeano AI, Boutouyrie P, Pannier B, et al. Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension 2006; 48(1): 80–6
Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006; 113(9): 1213–25
Boutouyrie P, Achouba A, Trunet P, et al. Amlodipinevalsartan combination decreases central systolic blood pressure more effectively than the amlodipine-atenolol combination: the EXPLOR study. Hypertension 2010; 55(6): 1314–22
London GM, Asmar RG, O’Rourke MF, et al. Mechanism(s) 2of selective systolic blood pressure reduction after a low-dose combination of perindopril/indapamide in hypertensive subjects: comparison with atenolol. J Am Coll Cardiol 2004; 43(1): 92–9
McEniery CM, Schmitt M, Qasem A, et al. Nebivolol increases arterial distensibility in vivo. Hypertension 2004; 44(3): 305–10
Dhakam Z, Yasmin, McEniery CM, et al. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens 2008; 26(2): 351–6
Mahmud A, Feely J. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am J Hypertens 2008; 21(6): 663–7
Rizos EC, Agouridis AP, Elisaf MS. The effect of statin therapy on arterial stiffness by measuring pulse wave velocity: a systematic review. Curr Vasc Pharmacol 2010; 8(5): 638–44
Van DS, McColl G, Wicks IP. Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis 2004; 63(12): 1571–5
Wallace SM, Maki-Petaja KM, Cheriyan J, et al. Simvastatin prevents inflammation-induced aortic stiffening and endothelial dysfunction. Br J Clin Pharmacol 2010; 70(6): 799–806
Fassett RG, Robertson IK, Ball MJ, et al. Effects of atorvastatin on arterial stiffness in chronic kidney disease: a randomised controlled trial. J Atheroscler Thromb 2010; 17(3): 235–41
Kool MJ, Lambert J, Stehouwer CD, et al. Vessel wall properties of large arteries in uncomplicated IDDM. Diabetes Care 1995; 18(5): 618–24
Van de Water JM, Falchuk SC, Toh SH, et al. Noninvasive assessment of vascular disease in the lower limbs of diabetics. J Cardiovasc Surg (Torino) 1980; 21(4): 469–74
Riley WA, Freedman DS, Higgs NA, et al. Decreased arterial elasticity associated with cardiovascular disease risk factors in the young. Bogalusa Heart Study. Arteriosclerosis 1986; 6(4): 378–86
Salomaa V, Riley W, Kark JD, et al. Non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 1995; 91(5): 1432–43
Stehouwer CD, Henry RM, Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia 2008; 51(4): 527–39
Asmar R. Effect of telmisartan on arterial distensibility and central blood pressure in patients with mild to moderate hypertension and type 2 diabetes mellitus. J Renin Angiotensin Aldosterone Syst 2001; 2 Suppl. 2: S8–11
Karalliedde J, Smith A, DeAngelis L, et al. Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering. Hypertension 2008; 51(6): 1617–23
Spoelstra-de Man AM, van Ittersum FJ, Schram MT, et al. Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension. J Hum Hypertens 2006; 20(8): 599–611
Jensen-Urstad KJ, Reichard PG, Rosfors JS, et al. Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM. Diabetes 1996; 45(9): 1253–8
McNulty M, Mahmud A, Feely J. Advanced glycation endproducts and arterial stiffness in hypertension. Am J Hypertens 2007; 20(3): 242–7
Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 2003; 21(1): 3–12
Wolffenbuttel BH, Boulanger CM, Crijns FR, et al. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci U S A 1998; 95(8): 4630–4
Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation endproduct crosslink breaker. Circulation 2001; 104(13): 1464–70
Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 2007; 25(3): 577–83
Agarwal N, Rice SP, Bolusani H, et al. Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: a randomized, placebo-controlled, crossover trial. J Clin Endocrinol Metab 2010; 95(2): 722–30
Yu J, Jin N, Wang G, et al. Peroxisome proliferator-activated receptor gamma agonist improves arterial stiffness in patients with type 2 diabetes mellitus and coronary artery disease. Metabolism 2007; 56(10): 1396–401
Nakamura T, Matsuda T, Kawagoe Y, et al. Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism 2004; 53(10): 1382–6
Araki T, Emoto M, Teramura M, et al. Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Metabolism 2006; 55(8): 996–1001
Ryan KE, McCance DR, Powell L, et al. Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. Atherosclerosis 2007; 194(2): e123–30
Oz O, Tuncel E, Eryilmaz S, et al. Arterial elasticity and plasma levels of adiponectin and leptin in type 2 diabetic patients treated with thiazolidinediones. Endocrine 2008; 33(1): 101–5
Harashima K, Hayashi J, Miwa T, et al. Long-term pioglitazone therapy improves arterial stiffness in patients with type 2 diabetes mellitus. Metabolism 2009; 58(6): 739–45
Kiyici S, Ersoy C, Kaderli A, et al. Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. Diabetes Res Clin Pract 2009; 86(1): 44–50
Mahmud A, Feely J. Adiponectin and arterial stiffness. Am J Hypertens 2005; 18 (12 Pt 1): 1543–8
Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 2005; 46(5): 1118–22
Maki-Petaja KM, Hall FC, Booth AD, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation 2006; 114(11): 1185–92
Amar J, Ruidavets JB, Sollier CB, et al. Relationship between C reactive protein and pulse pressure is not mediated by atherosclerosis or aortic stiffness. J Hypertens 2004; 22(2): 349–55
Maki-Petaja KM, Wilkinson IB. Anti-inflammatory drugs and statins for arterial stiffness reduction. Curr Pharm Des 2009; 15(3): 290–303
Wong M, Oakley SP, Young L, et al. Infliximab improves vascular stiffness in patients with rheumatoid arthritis. Ann Rheum Dis 2009; 68(8): 1277–84
Angel K, Provan SA, Gulseth HL, et al. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension 2010; 55(2): 333–8
Van DS, McColl G, Wicks IP. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology (Oxf) 2005; 44(11): 1428–32
Rajkumar C, Kingwell BA, Cameron JD, et al. Hormonal therapy increases arterial compliance in postmenopausal women. J Am Coll Cardiol 1997; 30(2): 350–6
Langrish JP, Mills NL, Bath LE, et al. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009; 53(5): 805–11
Rice SP, Agarwal N, Bolusani H, et al. Effects of dehydroepiandrosterone replacement on vascular function in primary and secondary adrenal insufficiency: a randomized crossover trial. J Clin Endocrinol Metab 2009; 94(6): 1966–72
Hemelaar M, van der Mooren MJ, van Baal WM, et al. Effects of transdermal and oral postmenopausal hormone therapy on vascular function: a randomized, placebo-controlled study in healthy postmenopausal women. Menopause 2005; 12(5): 526–35
Honisett SY, Pang B, Stojanovska L, et al. Progesterone does not influence vascular function in postmenopausal women. J Hypertens 2003; 21(6): 1145–9
Hayward CS, Samaras K, Campbell L, et al. Effect of combination hormone replacement therapy on ambulatory blood pressure and arterial stiffness in diabetic postmenopausal women. Am J Hypertens 2001; 14 (7 Pt 1): 699–703
Teede HJ, Liang YL, Kotsopoulos D, et al. A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function. Clin Endocrinol (Oxf) 2001; 55(5): 673–82
Westendorp IC, de Kleijn MJ, Bots ML, et al. The effect of hormone replacement therapy on arterial distensibility and compliance in perimenopausal women: a 2-year randomised trial. Atherosclerosis 2000; 152(1): 149–57
da Costa LS, de Oliveira MA, Rubim VS, et al. Effects of hormone replacement therapy or raloxifene on ambulatory blood pressure and arterial stiffness in treated hypertensive postmenopausal women. Am J Cardiol 2004; 94(11): 1453–6
Penotti M, Farina M, Castiglioni E, et al. Alteration in the pulsatility index values of the internal carotid and middle cerebral arteries after suspension of postmenopausal hormone replacement therapy: a randomized crossover study. Am J Obstet Gynecol 1996; 175 (3 Pt 1): 606–11
Bui MN, Arai AE, Hathaway L, et al. Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women. Am J Cardiol 2002; 90(1): 82–5
Giraud GD, Morton MJ, Wilson RA, et al. Effects of estrogen and progestin on aortic size and compliance in postmenopausal women. Am J Obstet Gynecol 1996; 174(6): 1708–17
Wilkinson IB, Megson IL, MacCallum H, et al. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. J Cardiovasc Pharmacol 1999; 34(5): 690–3
Vlachopoulos C, Dima I, Aznaouridis K, et al. Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals. Circulation 2005; 112(14): 2193–200
Hennerici MG, Bots ML, Ford I, et al. Rationale, design and population baseline characteristics of the PERFORM vascular project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial. Cardiovasc Drugs Ther 2010; 24(2): 175–80
Lacolley P, Challande P, Osborne-Pellegrin M, et al. Genetics and pathophysiology of arterial stiffness. Cardiovasc Res 2009; 81(4): 637–48
Cambien F, Tiret L. Genetics of cardiovascular diseases: from single mutations to the whole genome. Circulation 2007; 116(15): 1714–24
Levy D, Larson MG, Benjamin EJ, et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet 2007; 8 Suppl. 1: S3
Vlachopoulos C, Kosmopoulou F, Panagiotakos D, et al. Smoking and caffeine have a synergistic detrimental effect on aortic stiffness and wave reflections. J Am Coll Cardiol 2004; 44: 1911–7
Vlachopoulos C, Aznaouridis K, Alexopoulos N, et al. Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens 2005; 18: 785–91
Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and prevention. Hypertension 2009; 54(1): 3–10
Merideth MA, Gordon LB, Clauss S, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008; 358(6): 592–604
Dietz HC. New therapeutic approaches to mendelian disorders. N Engl J Med 2010; 363(9): 852–63
Yang SH, Qiao X, Fong LG, et al. Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation. Biochim Biophys Acta 2008; 1781(1-2): 36–9
Benetos A, Okuda K, Lajemi M, et al. Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension 2001; 37(2): 381–5
Aubert G, Lansdorp PM. Telomeres and aging. Physiol Rev 2008; 88(2): 557–79
Nawrot TS, Staessen JA, Holvoet P, et al. Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking. Front Biosci (Elite Ed) 2010; 2: 1164–8
Haller H, Ito S, Izzo Jr JL, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364(10): 907–17
Ong KT, Perdu J, De BJ, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010; 376(9751): 1476–84
Guerin AP, Blacher J, Pannier B, et al. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 2001; 103(7): 987–92
Acknowledgements
No sources of funding were used in the preparation of this manuscript. The authors have declared that they have no conflicts of interest that are directly related to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Boutouyrie, P., Lacolley, P., Briet, M. et al. Pharmacological Modulation of Arterial Stiffness. Drugs 71, 1689–1701 (2011). https://doi.org/10.2165/11593790-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11593790-000000000-00000