Journal of Human (2005) 19, 507–509 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh COMMENTARY Large stiffness and

CM McEniery and IB Wilkinson Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

Journal of Human Hypertension (2005) 19, 507–509. doi:10.1038/sj.jhh.1001814 Published online 13 January 2005

Atherosclerosis remains the leading cause of death risk.18 Increased large artery stiffness, as assessed by worldwide, and although the underlying pathophy- the aortic (PWV) or augmenta- siology is incompletely understood, it is increas- tion index (AIx), independently predicts cardiovas- ingly viewed as an inflammatory condition.1 Indeed, cular risk in a variety of populations.19–23 Stiffening levels of circulating white cells and inflammatory of the large may also predispose to athero- mediators, such as C-reactive protein (CRP) and sclerosis, in part, by changes in mechanical stress interleukin-6 (IL-6), are raised in patients with within the arterial wall and a reduction in shear , and in those with cardio- stress.24 Interestingly, brachial , a vascular risk factors, including a family history of surrogate measure of arterial stiffness, correlates premature cardiovascular disease.2 Moreover, when with CRP and interleukin-6 (IL6) levels in appar- assessed with highly sensitive assays, CRP levels ently healthy men.25,26 Serum CRP levels also independently predict outcome in patients with correlate with aortic PWV in subjects with end-stage coronary disease,3,4 and in apparently healthy renal failure.27 We have also demonstrated that individuals.5,6 More direct evidence concerning the role aortic PWV is increased in subjects with acute of inflammation in formation comes from antineutrophil cytoplasmic antibody-(ANCA) asso- in vitro studies and animal models of .1 ciated systemic (AASV) compared with Much mechanistic research in humans has fo- controls,28 and that PWV correlates with CRP. cused on the relationship between inflammation Interestingly, there was no difference between the and vascular function so-called ‘surrogate markers’ aortic PWV in controls and those subjects in such as endothelial function. Endothelial dysfunc- remission, raising the possibility that acute inflam- tion, or reduced nitric oxide bioavailability is mation is associated with a reversible increase in viewed as a key event in the development of arterial stiffness (Table 1). atheromatous plaques,7 and endothelial function is A number of studies have also demonstrated a an independent predictor of outcome in patients positive relationship between CRP and aortic PWV with cardiovascular disease8 or hypertension.9 Inter- in healthy, community-based individuals.29–31 The estingly, CRP levels correlate with endothelial paper by Duprez et al32 adds to this body of function in patients with coronary artery disease,10 literature by reporting an association between high and induction of acute inflammation by vaccination sensitivity CRP and an index of large artery results in endothelial dysfunction in humans,11 elasticity, termed C1, but not with C2—an index of which can be attenuated by co-administration of aspirin.12 We and others have also demonstrated endothelial dysfunction in patients with acute Table 1 Inflammation and stiffness systemic vasculitis13,14 and chronic inflammatory 15,16 What is known on this topic? conditions such as rheumatoid arthritis, which Arterial stiffness is an important predictor of risk are also associated with increased risk of cardiovas- Endothelial factors including nitric oxide influence arterial cular disease.17 Moreover, successful anti-inflamma- stiffness tory therapy in such patients can restore ‘normal’ Acute and chronic inflammation are associated with endothelial function.13,14 endothelial dysfunction in large and small arteries CRP correlates with brachial pulse pressure and aortic pulse- More recently, interest has focused on large artery wave velocity in healthy individuals stiffness as a surrogate measure of cardiovascular What does the study by Duprez et al add? HsCRP is associated with large, but not small, artery stiffness in Correspondence: Dr IB Wilkinson, Clinical Pharmacology Unit, asymptomatic individuals Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. Small artery stiffness is associated with an abnormal lipid E-mail: [email protected] profile, glucose and age Published online 13 January 2005 Commentary CM McEniery and IB Wilkinson 508 small artery elasticity—in an asymptomatic popula- 2 Lind L. Circulating markers of inflammation and tion. These data further support a link between atherosclerosis. Atherosclerosis 2003; 169: 203–214. inflammation and large artery stiffening. 3 Liuzzo G et al. The prognostic value of C-reactive Inflammation may stiffen the large arteries by a protein and serum amyloid a protein in severe unstable number of different mechanisms. We have recently angina. N Engl J Med 1994; 331: 417–424. 4 Ridker PM et al. Inflammation, pravastatin, and the demonstrated that a number of circulating and risk of coronary events after in endothelial-derived factors, including nitric oxide patients with average levels. Cholesterol and endothelin-1, influence large artery stiffness— and Recurrent Events (CARE) Investigators. Circula- providing so-called ‘functional’ regulation of arterial tion 1998; 98: 839–844. 33–35 stiffness. Inflammation is associated with en- 5 Ridker PM et al. Inflammation, aspirin, and the risk dothelial dysfunction,11,28 which may lead to func- of cardiovascular disease in apparently healthy men. tional stiffening of the large arteries due to reduced N Engl J Med 1997; 336: 973–979. nitric oxide bioavailability and increased activity of 6 Ridker PM et al. Comparison of C-reactive protein and opposing mediators such as endothelin-1. Such a low-density lipoprotein cholesterol levels in the pre- mechanism may also explain why acute vasculitis is diction of first cardiovascular events. N Engl J Med potentially associated with reversible stiffening. 2002; 347: 1557–1565. Endothelial dysfunction also leads to a number 7 Luscher TF. The Endothelium in Cardiovascular Dis- of changes in the extracellular matrix including ease. Springer-verlag: New York, 1995. 8 Suwaidi JA et al. Long-term follow-up of patients with smooth muscle cell proliferation and increased 36 mild coronary artery disease and endothelial dysfunc- synthesis of structural proteins including . tion. Circulation 2000; 101: 948–954. Therefore, chronic inflammation may lead to so- 9 Perticone F et al. Prognostic significance of endothelial called ‘structural’ stiffening of the larger vessels. An dysfunction in hypertensive patients. Circulation increase in circulating inflammatory mediators 2001; 104: 191–196. promotes white cell infiltration into arteries, and a 10 Fichtlscherer S et al. Elevated C-reactive protein levels change in vascular smooth muscle phenotype. Both and impaired endothelial vasoreactivity in patients these cell types release a number of inducible matrix with coronary artery disease. Circulation 2000; 102: metalloproteinases (MMP), including MMP-9, 1000–1006. which can degrade . Any loss of elastin or 11 Hingorani AD et al. Acute systemic inflammation elastic lamellae from the media could be expected to impairs endothelium-dependent dilatation in humans. result in arterial stiffening. Under inflammatory Circulation 2000; 102: 994–999. 12 Kharbanda RK et al. Prevention of inflammation- conditions, vascular smooth muscle cells also induced endothelial dysfunction: a novel vasculo- express osteoblast markers and can take up phos- protective action of aspirin. Circulation 2002; 105: phate to produce bioapatite, leading to medial 2600–2604. 37 calcification and reduced vessel elasticity. It is 13 Booth AD et al. Infliximab improves endothelial also likely that the proteoglycan composition and dysfunction in systemic vasculitis: a model of vascular state of hydration differs in the inflamed arterial inflammation. Circulation 2004; 109: 1718–1723. wall from that of normal vessels, thus altering the 14 Filer AD et al. Diffuse endothelial dysfunction biomechanical properties of large arteries. Finally, is common to ANCA associated systemic vasculitis perivascular inflammation and cellular infiltration and polyarteritis nodosa. Ann Rheum Dis 2003; 62: around the vasa vasorum may lead to vessel 162–167. ischaemia, particularly if there is thrombo-occlu- 15 Hurlimann D et al. Anti-tumor necrosis factor-alpha sion, which may also promote matrix remodelling treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002; 106: and ultimately stiffening of the vessels. 2184–2187. There is now good evidence that acute and low- 16 Bergholm R et al. Impaired responsiveness to NO in grade chronic inflammation are associated with newly diagnosed patients with rheumatoid arthritis. stiffening of the large arteries. This is likely to Arterioscler Thromb Vasc Biol 2002; 22: 1637–1641. promote atheroma formation and increase cardio- 17 Solomon DH et al. Cardiovascular morbidity and vascular risk. The exact mechanisms responsible for mortality in women diagnosed with rheumatoid arterial stiffening remain to be elucidated but are arthritis. Circulation 2003; 107: 1303–1307. likely to reflect both functional and structural 18 Arnett DK, Evans GW, Riley WA. Arterial stiffness: a changes in the vessel wall. Potentially, anti-inflam- new cardiovascular risk factor. Am J Epidemiol 1994; matory therapies may be useful in retarding or 140: 669–682. preventing arterial stiffening, and thus reducing 19 Blacher J et al. Impact of aortic stiffness on survival cardiovascular risk. in end-stage renal disease. Circulation 1999; 99: 2434–2439. 20 Laurent S et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37: References 1236–1241. 21 Meaume S et al. Aortic pulse wave velocity predicts 1 Libby P. Inflammation in atherosclerosis. Nature 2002; cardiovascular mortality in subjects 470 years of age. 420: 868–874. Arterioscler Thromb Vasc Biol 2001; 21: 2046–2050.

Journal of Human Hypertension Commentary CM McEniery and IB Wilkinson 509 22 Cruickshank K et al. Aortic pulse-wave velocity and its individuals. Arterioscler Thromb Vasc Biol 2004; 24: relationship to mortality in and glucose 969–974. intolerance: an integrated index of vascular function? 30 Okamura T et al. Non-invasive measurement of Circulation 2002; 106: 2085–2090. brachial-ankle pulse wave velocity is associated with 23 London GM et al. Arterial wave reflections and serum C-reactive protein but not with alpha-tocopher- survival in end-stage renal failure. Hypertension ol in Japanese middle-aged male workers. Hypertens 2001; 38: 434–438. Res 2004; 27: 173–180. 24 Glasser SP et al. Vascular compliance and cardiovas- 31 Mattace-Raso FU et al. C-reactive protein and arterial cular disease: a risk factor or a marker? Am J Hypertens stiffness in older adults: the Rotterdam Study. Athero- 1997; 10: 1175–1189. sclerosis 2004; 176: 111–116. 25 Abramson JL, Weintraub WS, Vaccarino V. Association 32 Duprez D et al. Relationship between C-reactive between pulse pressure and C-reactive protein among protein and arterial stiffness in an asymptomatic apparently healthy US adults. Hypertension 2002; 39: population. J Hum Hypertens 2005; 19: 515–519. 197–202. 33 Wilkinson IB et al. Nitric oxide regulates local arterial 26 Chae CU, Lee RT, Rifai N, Ridker PM. distensibility in vivo. Circulation 2002; 105: 213–217. and inflammation in apparently healthy men. Hyper- 34 McEniery CM et al. Endothelin-1 regulates arterial tension 2001; 38: 399–403. pulse wave velocity in vivo. J Am Coll Cardiol 2003; 27 London GM et al. Inflammation, , and 42: 1975–1981. cardiovascular therapy in hemodialysis patients. Kid- 35 Schmitt M et al. Role of natriuretic peptides in ney Int Suppl 2003; 84: 88–93. regulation of conduit artery distensibility. Am J Physiol 28 Booth AD et al. Inflammation and arterial stiffness in Heart Circ Physiol 2004; 287: H1167–H1171. systemic vasculitis: a model of vascular inflammation. 36 The Molecular Biology and Pathology of Elastic Arthritis Rheum 2004; 50: 581–588. Tissues.John Wiley & Sons: Chichester, 1995. 29 Yasmin, McEniery CM, Wallace S, Mackenzie IS, 37 Floege J, Ketteler M. Vascular calcification in patients Cockcroft JR, Wilkinson IB. C-reactive protein is with end-stage renal disease. Nephrol Dial Transplant associated with arterial stiffness in apparently healthy 2004; 19(Suppl 5): V59–V66.

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