Fig. 1. Predictive value for fatal stroke of pulse wave velocity (PWV) in essential hypertensive patients [from 36].
Fig. 1. Predictive value for fatal stroke of pulse wave velocity (PWV) in essential hypertensive patients [from 36].
Brachial pulse pressure (instead of carotid pulse pressure) is used for the calculation of all these parameters and this may reduce their precision. Despite this limitation, all these parameters are well accepted as indices of arterial stiffness  .
Cross-sectional studies have shown a significant correlation between arterial stiffness and CV risk factors for atherosclerotic lesions, such as aging, hypertension, hypercholesterolemia, type 2 diabetes mellitus or glucose intolerance, metabolic syndrome, and several inflammation parameters, suggesting that arterial stiffness may be considered a marker of CV risk .
In addition, longitudinal studies have evaluated the incidence of cardiovascular events, including stroke, during follow-up, and have demonstrated the predictive value of arterial stiffness as an intermediate endpoint.
Longitudinal studies directly demonstrated that arterial stiffness, measured through carotid-femoral PWV, was an independent predictor of stroke  in patients with uncomplicated essential hypertension. In a population of 1,715 essential hypertensive patients, Laurent et al.  have found that after a mean follow-up of 7.9 years, for each SD increase in PWV (4 m/s) the relative risk for fatal stroke increased by 1.72 (95% CI 1.48-1.96; p > 0.0001). The predictive value of PWV remained significant (RR = 1.39; 95% CI 1.08-1.72; p > 0.02) after full adjustment for classic cardiovascular risk factors, including age, cholesterol, diabetes, smoking, mean arterial pressure, and pulse pressure (fig. 1).
Additional evidence of the predictive value of aortic stiffness was provided in patients with end-stage renal disease, although cardiovascular events, i.e. stroke or coronary disease, were not analyzed separately .
In 2,488 older subjects participating into the Health, Aging and Body Composition (Health ABC) study , aortic PWV was measured at baseline and during the follow-up (over 4.6 years) and 94 stroke events were recorded. The higher quartiles of aortic PWV were significantly associated with an increased risk of stroke, and the association remained statistically significant also after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events.
In summary, a significant association between the increase in aortic stiffness and the incidence of cerebrovascular (and cardiovascular) events has been demonstrated, independently from other traditional risk factors. In patients with end-stage renal disease it has also been reported that the lack of decrease in PWV during antihypertensive treatment was associated with a higher cardiovascular mortality, while the improvement of PWV was associated with a lower incidence of cardiovascular events .
In addition to aortic stiffness, it may be also important to assess the prognostic significance of carotid stiffness. In stiff carotid arteries the local pulse pressure is increased, and this may influence structural and functional changes of intracranial vessels. Higher local pulse pressure may increase the carotid wall thickness and favor the development of plaques and stenosis, as well as the rupture of unstable plaque.
In patients with end-stage renal disease and with kidney transplantation [38, 40], but not in patients at elevated cardiovascular risk , carotid stiffness had a high predictive power for future cardiovascular fatal events, and for ischemic stroke as well.
The pathophysiological mechanisms relating aortic and carotid stiffness to stroke include the association with similar risk factors , and the alterations in the vascular wall of aorta that may reflect those in cerebral vessels; in addition, both the carotid arteries and the aorta may be exposed to other pathological mechanisms, such as thrombosis and inflammation .
Future trials should provide measurements of both aortic and carotid stiffness in low or moderate CV risk populations, in order to better evaluate their relative prognostic value for cerebrovascular and coronary events.
It is conceivable that the reduction of arterial stiffness may become a therapeutic goal in treating patients at high risk of CV complications [44, 45]. In this regard, an important issue is represented by the ability of different drugs to prevent cardiovascular events by improving arterial distensibility, even independently of the effect on other risk factors.
Organic nitrates, and in particular nitroglycerin, reduce systolic blood pressure, pulse pressure and augmentation index, but have a small effect on peripheral arterial resistance, or on aortic PWV. In fact, organic nitrates may improve symptoms, without modifying mortality or cardiovascular events.
It is generally accepted that ACE inhibitors, calcium antagonists and diuretics may similarly affect large artery stiffness in hypertensive patients, while P-blockers are less effective in this regard . ^-Blockers do not reduce central arterial waveform reflection amplitude, while a reduction of the augmentation index has been documented during treatment with P- and a-block-ers. The effect of drugs that interfere with the renin-angiotensin system (ACE inhibitors, aldosterone antagonists and angiotensin II antagonists) seems to be, at least in part, independent of blood pressure reduction, since they modify the composition of the vascular wall, including the spatial arrangement of wall material and the collagen content [46-51].
The augmentation index can be reduced by vasodilating drugs and by an-giotensin-converting enzyme (ACE) inhibitors in both essential hypertensive patients and in patients with end-stage renal failure. The low-dose combination of the ACE inhibitor perindopril and the diuretic indapamide, in comparison with atenolol, induced a more pronounced effect on central arterial pressure and was associated to a greater decrease in LV mass .
The observed effect of ACE inhibitors (and possibly of angiotensin II antagonists) is to some degree influenced by genetic factors [52, 53], since ACE ID and A1166C angiotensin II type 1 receptor polymorphisms are related to carotid-femoral PWV, while M235T angiotensinogen gene and ACE ID polymorphisms are related to carotid stiffness.
In patients with familiar hypercholesterolemia, pravastatin was able to improve arterial stiffness after 13 months of treatment , while atorvastatin had no significant effect on carotid stiffness. In non-familiar hypercholester-olemia, short-term treatment with simvastatin did not change aorto-femoral PWV.
In addition, treatment for 2 months with a new compound, that acts as an advanced glycation product cross-link breaker, has been beneficial in ameliorating PWV .
Carotid atherosclerosis and arterial stiffness are both related to risk factors associated with the occurrence of stroke. These two markers of 'preclinical' vascular disease are related to the occurrence of stroke independently of other cardiovascular risk factors. Assessment of IMT or of measures of large arteries compliance may therefore identify patients at increased risk for stroke.
Interventional studies have demonstrated that treatment with statins, calcium antagonists, ACE inhibitors, and insulin sensitizers may be particularly effective on slowing the progression or favoring the regression of atherosclerotic changes, and may reduce large artery stiffness. It remains to be demonstrated in large prospective studies whether the regression of increased arterial stiffness or of carotid IMT and plaque have a prognostic significance, i.e. are associated with a reduction of the risk of cerebrovascular events.
1 Mancini JGB, Dahlof B, Diéz J: Surrogate markers for cardiovascular disease. Structural markers. Circulation 2004;109(suppl IV):IV-22-IV-30.
2 Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J: Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159-169.
3 Laurent S: Arterial stiffness intermediate or surrogate endpoint for cardiovascular events. Eur Heart J 2005;26:1152-1154.
4 Oliver J, Webb DJ: Non-invasive assessment of arterial stiffness and the risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003;23:554-566.
5 Muiesan ML, Pasini GF, Salvetti M, Calebich S, Zulli R, Castellano M, Rizzoni D, et al: Cardiac and vascular structural changes: prevalence and relation to ambulatory blood pressure in a middle-aged general population in northern Italy: the Vobarno Study. Hypertension 1996;27:1046-1053.
6 Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R: Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients: A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis 1988;70:253-261.
7 Bots M, Evans GW, Riley WA, Grobbee DE: Carotid intima-media thickness measurements in intervention studies design options, progression rates, and sample size considerations: a point of view. Stroke 2003;34:2985-2994.
8 Baldassarre D, Amato M, Bondioli A, Sirtori C, Tremoli E: Carotid intima-media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerotic risk factors. Stroke 2000;31:2426-2430.
9 Zureik M, Ducimetiere P, Touboul PJ, Courbon D, Bonithon-Kopp C, Berr C, Magne C: Common carotid predicts occurrence of carotid atherosclerotic plaques: longitudinal results from the Aging Vascular Study (EVA) study. Arterioscler Thromb Vasc Biol 2000;20:1622-1629.
10 Salonen R, Haapanen A, Salonen JT: Measurement of intima-media thickness of common carotid arteries with high resolution B-mode ultrasonography: inter- and intra-observer variability. Ultrasound Med Biol 1991;17:225-230.
11 Furberg CD, Adams HP Jr, Applegate WB, Byington RB, Espeland MA, Hartwell T, et al: Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1994;90:1679-1687.
12 Borhani NO, Mercuri M, Borhani PA, Buckalow VM, et al: Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). JAMA 1996;276:785-791.
13 Tang R, Henning M, Thomasson B; Scherz R, Ravinetto R, Cattalini R, et al: Baseline reproduc-ibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2000;18:197-201.
14 Zanchetti A, Bond G, Hennig M, Neiss A, Mancia G, Dal Palü C, Hansson L, Magnani B, Rahn KH, Reid J, Rodicio J, Safar M, Eckes L, Ravinetto R on behalf of the ELSA Investigators: Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J Hypertens 1998;16:949-961.
15 Touboul P, Labreuche J, Vicaeut E, Amarenco P, on behalf of the GENIC Investigators: Carotid intima-media thickness, plaque and Framingham risk score are independent determinants of stroke risk. Stroke 2005;36:1741-1745.
16 Norris JW, Zhu CZ, Bornstein NM, Chambers BR: Vascular risks of asymptomatic carotid stenosis. Stroke 1991;22:1485-1490.
17 Longstreth WT Jr, Shemanski L, Lefkowitz D, O'Leary DH, Polak JF, Wolfson SK Jr: Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study. Stroke 1998;29:2371-2376.
18 Chambeless LE, Folsom AR, Clegg LX, Sharret AR, Shahar E, Nieto FJ, Rosamond W, Evans G: Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 2000;151:478-487.
19 Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE: Common carotid intima-media thickness and risk of stroke and myocardial infarction the Rotterdam study. Circulation 1997;6: 1432-1437.
20 O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK for the Cardiovascular Health Study Collaborative Research Group: Carotid intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999;340:14-22.
21 Zanchetti A, Agabiti-Rosei E, Dal Palü' C, Leonetti G, Magnani B, Pessina A, for the Verapamil in Hypertension and Atherosclerosis Study (VHAS) Investigators: The VHAS: results of long-term randomized treatment with either verapamil or chlortalidone on carotid intima-media thickness. J Hypertens 1998;16:1667-1676.
22 Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palü C, et al: Calcium antagonist la-cidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002;106:2422-2427.
23 Simon A, Gariepy J, Moyse D, Levenson J: Differential effects of nifedipine and co-amilozide on the progression of early carotid atherosclerosis. A four-year randomised, controlled clinical study of intima-media thickness measured by ultrasound. Circulation 2001;103:2949-2954.
24 Stanton AV, Chapman JN, Mayet J, Sever PS, Poulter NR, Hughes AD, Thom SA: Effects of blood pressure lowering with amlodipine or lisinopril on vascular structure of the common carotid artery. Clin Sci 2001;101:455-464.
25 Stumpe KO, Ludwig M: Antihypertensive efficacy of olmesartan compared with other antihypertensive drugs. J Hum Hypertens 2002; 16, S24-S28.
26 Paliotti R, Ciulla M, Hennig M, Tang R, Bond G, Mancia G, Magrini F, Zanchetti A: Carotid wall composition in hypertensive patients after 4-year treatment with lacidipine or atenolol: an echoreflectivity study J Hypertens 2005;23:1203-1209.
27 Zanchetti A, Crepaldi G, Bond G, Gallus G, Veglia F, Mancia G, Ventura S, Baggio G, Sampietri L, Rubba P, Sperti G, Magni A on behalf of PHYLLIS Investigators: Different effects of antihy-pertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis principal results of PHYLLIS - a randomized double-blind trial. Stroke 2004;35:2807-2812.
28 Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W (for The PREVENT Investigators): Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000;102:1503-1510.
29 Lonn EM, Yusuf S, Dzivik V, Doris CI, Yi Q, Smith S, et al: Effect of ramipril and vitamin E on atherosclerosis. The study to evaluate ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 2001;103:919-925.
30 Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G: Low-dose metoprolol CR/XL and flu-vastatin slow progression of carotid intima-media thickness: main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001; 103:17211726.
31 Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Fagard R, Messerli FH, Safar M: Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials. Stroke 2006;37:1933-1940.
32 Amarenco P, Labreuche J, Lavallee P, Touboul PJ: Statins in stroke prevention and carotid atherosclerosis. Systematic review and up-to-date meta-analysis. Stroke 2004;35:2902-2909.
33 Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, Fullert SD, Sachara C, Pfutzner A: Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 2005;111:2525-2531.
34 De Kleijn MJ, Bots ML, Bak AA, Westendorp IC, Planellas J, Coelingh Bennink HJ, et al: Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness. Maturitas 1999;32:195-204.
35 Pannier BM, Avolio AP, Hoeks A, Mancia G, Takazawa K: Methods and devices for measuring arterial compliance in humans. Am J Hypertens 2002;15:743-753.
36 Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P: Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003;34:1203-1206.
37 Blacher J, Pannier B, Guerin A, Marchais SJ, Safar ME, London GM: Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease. Hypertension 1998;32:570-574.
38 Sutton-Tyrrell K, Najjar S, Boudreau R, Venkitachalam L, Kupelian V, Simonsick E, Havlik R, Lakatta E, Spurgeon H, Kritchevsky S, Pahor M, Bauer D, Newman A, for the Health ABC Study: Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005;111:3384-3390.
39 Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 2001;20:987-992.
40 Barenbrock M, Kosh M, Joster E, Kisters K, Rhan KH, Hausberg M: Reduced arterial distensibil-ity is a predictor of cardiovascular disease in patients after renal transplantation. J Hypertens 2002;20:79-84.
41 Dijk JM, Algra A, van der Graaf Y, Grobbee DE, Bots ML, on behalf of the SMART Study Group: Carotid stiffness and the risk of new vascular events in patients with manifest cardiovascular disease. The SMART study. Eur Heart J doi:10.1093/eurheartj/ehi254.
42 Dijk JM, van der Graaf Y, Grobbee DE, Bots ML, on behalf of the SMART Study Group: Carotid stiffness indicates risk of ischemic stroke and TIA in patients with internal carotid artery stenosis. The SMART study. Stroke 2004;35:2258-2262.
43 Mahmud A, Feely J: Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 2005;46:1118-1122.
44 Laurent S, Boutouyrie P: Arterial stiffness and stroke in hypertension: therapeutic implications for stroke prevention. CNS Drugs 2005;19:1-11.
45 Laurent S, Kingwell B, Bank A, et al: Clinical applications of arterial stiffness: Therapeutic and pharmacology. Am J Hypertens 2002;15:453-458.
46 Safar ME, Van Bortel LMAB, Struijker Boudier HAJ: Resistance and conduit arteries following converting enzyme inhibition in hypertension. J Vasc Res 1997;34:67-81.
47 Benetos A, Lacolley P, Safar M: Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. J Hypertens 1995;13:839-848.
48 Blacher J, Amah G, Girerd X, et al: Association between effects of antihypertensive drugs on arterial reflections, compliance and impedance. Hypertension 1995;26:524-530.
49 Lacolley P, Labat C, Pujol A, et al: Increased carotid wall compliance after long-term antihypertensive treatment: The effects of eplerenone. Circulation 2002; 106:2848-2853.
50 Asmar RG, London GM, O'Rourke ME, et al: Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001;38:922-926.
51 Morgan T, Lauri J, Bertram D, Anderson A: Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 2004;17:118-123.
52 Laurent S, Boutouyrie P, Lacolley P: Structural and genetic bases of arterial stiffness. Hypertension 2005;45:1050-1055.
53 Manolio TA, Boerwinkle E, O'Donnel CJ, Wilson A: Genetics of ultrasonographic carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:1567-1577.
54 Giannattasio C, Mangoni AA, Failla M, et al: Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia. Atherosclerosis 1996; 124:249-260.
55 Kass DA, Shapiro EP, Kawaguchi M, et al: Improved arterial compliance by a novel advanced glycation end-product cross-link breaker. Circulation 2001; 104:1464-1470.
Prof. Enrico Agabiti-Rosei, Chair of Internal Medicine
Department of Medical and Surgical Sciences, University of Brescia c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, IT-25100 Brescia (Italy)
Tel. +39 030 396 044, Fax +39 030 338 8147, E-Mail [email protected]
Section II - Arterial Stiffness, Atherosclerosis and End-Organ Damage
Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 187-198
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