Association between pulse pressure, carotid intima media thickness and carotid and/or iliofemoral plaque in hypertensive patients

Transcription

1 (2004) 18, & 2004 Nature Publishing Group All rights reserved /04 $ ORIGINAL ARTICLE Association between pulse pressure, carotid intima media thickness and carotid and/or iliofemoral plaque in hypertensive patients J-M Tartière 1, L Kesri 1, H Safar 2, X Girerd 2, M Bots 3, ME Safar 2 and J Blacher 2 1 Department of Cardiology, Beaujon Hospital, Clichy, France; 2 Department of Internal Medicine, Broussais Hospital, AP-HP, Paris, France; 3 Universitair Medisch Centrum, Utrecht, the Netherlands Increased common carotid artery intima media thickness (CCA-IMT) and carotid and/or iliofemoral (C/IF) plaque are frequent in subjects treated for hypertension, but their association with pulse pressure (PP) has rarely been studied. Using ultrasound techniques, CCA-IMT and C/IF plaques were studied in 323 hypertensive subjects, who were classified into four groups according to the adequacy of blood pressure (BP) control (systolic BP (SBP) o140 mmhg and diastolic BP (DBP) o90 mmhg) and PP (high or low). After adjustment for confounding variables, an increase in CCA-IMT was the only factor significantly and independently associated with high PP, irrespective of the effectiveness of blood pressure control and of antihypertensive drug treatment. CCA-IMT correlated with age, PP, waist-to-hip ratio, tobacco consumption, and heart rate. C/IF plaques correlated with age, tobacco consumption, diabetes mellitus, and dyslipidaemia. To conclude, even with SBPo140 mmhg and DBPo90 mmhg on treatment, hypertensive subjects may have increased CCA-IMT values and C/IF plaque. Four cardiovascular risk factors seem to be involved in these alterations, namely tobacco consumption, dyslipidaemia, diabetes and increased PP. Only the latter factor does not have a standardized effective treatment. (2004) 18, doi: /sj.jhh Published online 29 January 2004 Keywords: atherosclerosis; pulse pressure; arterial thickness; arterial plaques Introduction Increased common carotid artery intima media thickness (CCA-IMT) and presence of arterial plaques are significantly associated with cardiovascular risk factors. 1 6 In most recent prospective studies, CCA-IMT and/or aortic abdominal calcifications significantly predicted the occurrence of cardiovascular events. 7,8 PP, a significant independent marker of cardiovascular mortality, 9,10 has been found in many experimental and clinical studies to modulate IMT The EVA study 12 showed both crosssectional and longitudinal associations between brachial PP and CCA-IMT in humans. Moreover, CCA-IMT and plaques seem to be complementary in the assessment of cardiovascular risk in hypertensive patients. 15 We have postulated Correspondence: Dr J-M Tartière, Hôpital Beaujon, Service de Cardiologie, 100 Bd Gal Leclerc, Clichy 92118, France. jean-michel.tartiere@bjn.ap-hop-paris.fr Received 30 June 2003; revised 03 November 2003; accepted 11 November 2003; published online 29 January 2004 that CCA-IMT and arterial plaques could correlate differently with cardiovascular risk factors. We examined treated and untreated hypertensive subjects in order to determine the crude and adjusted association between CCA-IMT or carotid and/or iliofemoral (C/IF) plaques and blood pressure (BP). Hypertensive subjects were classified not only according to the adequacy of BP control (systolic BP (SBPo140 mmhg and diastolic BP (DBP) o90 mmhg) but also according to the presence of low or high (460 mmhg) pulse pressure (PP) on drug treatment. We therefore analysed many of the factors influencing CCA-IMT, carotid geometry, and C/IF plaques, and specifically their relationship with PP. Methods Study cohort From December 2000 to June 2001, around 400 patients attended the Department of Internal Medicine of Broussais Hospital for a cardiovascular

2 326 check-up prescribed by their general practitioner or their cardiologist because of one or several cardiovascular risk factors, comprising high BP, smoking, dyslipidaemia, diabetes mellitus, and/or a family history of cardiovascular disease (CVD), with or without previously identified cardiovascular events. Of these 400 patients, subjects without hypertension (n ¼ 46) and those with secondary hypertension (n ¼ 31) were excluded on the basis of standard laboratory tests and radiological findings. In nevertreated hypertensive subjects (n ¼ 34), high BP was defined as SBPX140 mmhg and/or DBPX90 mmhg, measured by sphygmomanometry (see below). Hypertensive subjects (n ¼ 289) were included regardless of whether BP was well controlled (SBPo140 mmhg and DBPo90 mmhg). The study cohort was thus composed of 323 consecutive hypertensive patients (200 men, 123 women) with a mean age (7standard deviation) of years. Of these 323 subjects, 289 (89%) were on antihypertensive drug therapy at inclusion (mean antihypertensive drugs per patient). The antihypertensive drugs included calcium antagonists (n ¼ 163), beta blockers (n ¼ 109), diuretics (n ¼ 151), angiotensin-converting enzyme inhibitors (n ¼ 83), angiotensin II antagonists (n ¼ 49), centrally acting agents (n ¼ 53) and alpha blockers (n ¼ 16), either alone or in combination. A total of 104 patients (32%) were treated for dyslipidaemia (drugs including statins or fibrates). In all, 35 patients were medically treated for diabetes mellitus (drugs including sulphanylurea, biguanides, acarboses and insulin). In total, 72 (22%) patients were on aspirin. Each patient gave informed consent for the study, which was approved by our institutional review board. Information compiled from the questionnaire filled out at inclusion included gender, age, weight and height, body mass index, family history (firstdegree relatives) of premature cardiovascular events (o55 years in men and o65 years in women), personal history and duration of diabetes mellitus, personal history of dyslipidaemia, smoking habits, use of medications (including cardiovascular agents), and hormone replacement therapy in women. From the clinical questionnaire and the findings of radiology and ultrasonography performed during hospitalization, CVD was diagnosed in 96 patients and was ruled out in 227 patients. To describe CVD in hypertensive patients, we used the usual criteria according to the International Classification of Diseases (9th revision), for coronary heart disease, cerebrovascular disease, peripheral vascular disease, and abdominal aortic aneurysm. Dyslipidaemia was defined by the use of a lipid-lowering agent and/or according to usual consensus reports. 16 Uncontrolled dyslipidaemia was defined by an LDLcholesterol level over the goal of drug treatment introduction according to the usual consensus reports. 16 Diabetes mellitus was defined as a fasting blood glucose value 47.0 mmol/l or the use of hypoglycaemic agents. Uncontrolled diabetes mellitus was defined as a fasting blood glucose 47.0 mmol/l. In total, 96 patients had one or more CVD, including coronary heart disease (n ¼ 36), peripheral vascular disease (n ¼ 19), heart failure (n ¼ 14), supra-aortic vascular disease (n ¼ 30), stroke (n ¼ 19), abdominal aortic aneurysm (n ¼ 11), and insignificant atherosclerotic renal artery stenosis (n ¼ 10). The mean number of cardiovascular diseases per patient was (mean7standard deviation). Clinical and biological measurements Brachial BP was measured with a mercury sphygmomanometer after 10 min of rest, in the morning, in the supine position. Phases I and V of the Korotkoff sounds were considered, respectively, as SBP and DBP. The mean BP (MBP) was calculated as MBP ¼ (SBP þ 2 DBP)/3. PP was calculated as PP ¼ SBP DBP. The heart rate was measured simultaneously. For BP and heart rate, three measurements 2 min apart were averaged. The overall population was divided into four groups according to controlled BP (SBPo140 and DBPo90 mmhg) or uncontrolled BP (SBPX140 mmhg and/or DBPX90 mmhg) and low PP or high PP (PP460 mmhg). The 60 mmhg PP value was chosen as the cutpoint of epidemiological data corresponding to a significant PP-induced increase in cardiovascular risk. 9,17,18 Venous blood samples were obtained after an overnight fast. Plasma was separated without delay at 41C in a refrigerated centrifuge and stored at 41C until routine chemical analysis by standard methods. Cholesterol and triglyceride concentrations in serum, and HDL, were assayed by standard techniques; LDL cholesterol was calculated by using Friedwald s formula. 19 Ultrasonography Ultrasound examinations of the carotid and femoral arteries were performed with the patient in the recumbent position. We used a Sigma 110 KON- TRON device (Kontron Instruments, Paris) with a transducer frequency of 7.5 MHz. This system provides an axial resolution of 0.30 mm. Acquisition and storage of B-mode images were performed using M Ath Std software. 20 All measurements were made by one sonographer (JMT) at the time of examination (online) and were not blinded for BP collection. Measurements involved primary transversal and longitudinal scanning of the common carotid artery, and the bifurcation and origin (first 2 cm) of the internal carotid arteries. CCA-IMT was measured on the far wall of the middle section of the CCA, as the distance between the lumen intima interface and

3 the media adventitia interface, using an automated edge-detection algorithm. 21 One longitudinal measurement of IMT was completed in the right and left CCAs (segment410 mm, quality index450%), and the maximal CCA-IMT was the largest IMT, irrespectively of the side. For a 10-mm segment, which permits around 100 IMT measurements, the quality index was good when more than 50 values were obtained. CCA lumen diameter was measured on the same image. All measurements were made at a site free of plaque (even discrete). The CCA-IMT/radius ratio was defined as the CCA-IMT value divided by the CCA radius. The near and far walls of the carotid and iliofemoral arteries (common iliac and common femoral arteries including bifurcation) were scanned longitudinally and transversally for plaques, which were defined as localized echo structures encroaching into the vessel lumen, for which the distance between the media adventitia interface and the internal side of the lesion was greater than 1 mm 12 (or as the presence of calcifications). Each of the four sites (two carotid and two iliofemoral) was scored 1 or 0, respectively, for the presence or absence of one or more plaques. The number of sites with plaques was the sum of the four sites (total score 0 4). All measurements were made by the same observer (JMT). Intraobserver variability has been reported elsewhere. 15 Statistical analysis Statistical analyses were performed with NCSS software. 22 Variables with a skewed distribution (maximal CCA-IMT, CCA-lumen diameter, CCA- IMT/radius ratio, PP, plasma creatinine and plasma glucose) were log-transformed to achieve normal distribution, and these transformed variables were used in all analyses. A value of Po0.05 was considered significant for a two-tailed comparison. Data are expressed as means7standard error of the mean (s.e.m.). Relations between BP control or the presence of high or low PP and interaction, with clinical and vascular parameters were tested by twoway ANOVA. Adjustments were made on each variable significant in univariate analysis, and groups were tested by two-way ANCOVA. Stepwise regression was used to identify clinical and biological parameters influencing plaques and CCA-IMT. Results Tables 1 3 show the age- and sex-adjusted characteristics of the patients, as classified into four groups according to controlled/uncontrolled hypertension and high/low PP. Controlled (P ¼ 0.02) and uncontrolled diabetes mellitus (P ¼ 0.02), high CCA- IMT (P ¼ ), and high CCA-lumen diameter (P ¼ 0.01) were associated with high PP, regardless of BP control, and did not significantly interact. High SBP, MBP and PP, and low DBP, were associated with uncontrolled BP and high PP, with significant interactions for mostly SBP and PP. Iliofemoral or carotid or C/IF plaque was not associated with BP control or high PP. The CCA- IMT/radius ratio was associated with BP control and high PP (P ¼ 0.006). Renin angiotensin inhibitors were associated with better BP control (P ¼ 0.02), and aspirin use tended to be more frequent in patients with high PP. 327 Table 1 Clinical characteristics of the patients, after adjustment for age and sex, according to BP control (controlled BP ¼ SBPo140 mmhg and DBPo90 mmhg) and pp (high/low, see text) n ¼ 70 n ¼ 26 n ¼ 50 n ¼ 177 Duration of hypertension (years) Body height (cm) Weight (kg) Waist-to-hip ratio Plasma creatinine (mmol/l) SBP (mmhg) * o o DBP (mmhg) o o MBP (mmhg) * o PP (mmhg) * o o Heart rate (b.p.m.) Tobacco (pack-year) Diabetes mellitus (%) Uncontrolled diabetes mellitus (%) Dyslipidaemia (%) Uncontrolled dyslipidaemia (%) * Past history of CVD (%) Family history of CVD (%) *Po0.05 for interaction.

4 328 Table 2 Arterial parameters, adjusted for age and sex, according to according to BP control and PP CCA-IMT (mm) C/IF plaques (0 4) CCA plaques (0 2) Iliofemoral plaques (0 2) a CCA-diameter (mm) CCA-IMT/radius ratio a Po0.05 for interaction. Table 3 Drug treatment (age and sex adjusted) of hypertensive patients according to BP control and (pp) Diuretics (%) Beta-blockers (%) Calcium antagonists (%) Renin angiotensin inhibitors a (%) Other antihypertensive drugs (%) Lipid-lowering therapy (%) Aspirin (%) a Converting enzyme inhibitors or angiotensin II antagonists. Table 4 CCA parameters and drug treatment according to BP control and PP, after adjustment for age, gender, hypertension duration, body height, tobacco (life-long dose), uncontrolled diabetes mellitus, and dyslipidaemia, and drug therapy CCA-IMT (mm) C/IF plaques (0 4) CCA plaques (0 2) Iliofemoral plaques (0 2) CCA-Diameter (mm) CCA-IMT/radius ratio Table 4 showed adjusted values of CCA-IMT and C/IF plaques in the four categories of subjects. With the exception of the CCA-IMT/radius ratio, the blood pressure control did not significantly influence these parameters. After adjustment, high PP was significantly associated with increased CCA- IMT (P ¼ 0.007) but not with C/IF plaques. Table 5 shows the clinical and biological factors modulating the presence or the extent of plaques and the level of CCA-IMT. In addition to age and gender, C/IF plaques were significantly associated with tobacco consumption, dyslipidaemia and uncontrolled diabetes, but not with increased PP. CCA- IMT was associated with age, PP, waist-to-hip ratio, tobacco consumption, and heart rate. Discussion In this cross-sectional study of 323 chronically treated hypertensive subjects, CCA-IMT and C/IF plaques were more frequent in subjects with increased PP, independently of SBP and DBP control. After adjustment for confounding factors and drug therapy, only the association between PP and CCA-IMT persisted. A different pattern was observed between C/IF plaques and CCA-IMT. Indeed, C/IF plaques were independently and significantly associated with atherosclerotic risk factors such as dyslipidaemia, diabetes, and tobacco consumption. Increased CCA-IMT was associated with age, cardiovascular risks factors, and increased

5 Table 5 Factors influencing C/IF plaques and CCA-IMT PP. High PP was not associated with a past history of CVD. Methodological considerations Coefficient r 2 P C/IF plaques Age (years) o0.001 Gender (men ¼ 0, women ¼ 1) o0.001 Tobacco (pack-year) o0.001 Dyslipidaemia Uncontrolled diabetes R 2 ¼ CCA-IMT Age (years) o0.001 PP (mmhg) o0.001 Waist to hip ratio o0.001 Tobacco (pack-year) HR (b.p.m.) R 2 ¼ HR, heart rate. The study population consisted of patients attending the Department of Internal Medicine of Broussais Hospital for cardiovascular check-up, in conditions close to those of standard clinical practice, and most were elderly and on antihypertensive treatment. Although a significant proportion of patients (30%) had confirmed CVD, this proportion was probably underestimated, including unrecognized silent myocardial ischaemia or peripheral artery disease, as invasive investigations were not conducted routinely. We used brachial MBP and PP as independent markers of mechanical forces acting on the arterial wall. It is well established that MBP remains fairly constant throughout the length of the arterial tree, but PP is physiologically higher in the peripheral than in the central arteries. 23 Thus, the use of brachial PP as a measure of a cyclic force acting on the CCA wall may be questioned. However, the PP gradient along the entire arterial tree normally tends to disappear with age, due to a greater increase in PP with age in the aortic and central arteries than in the peripheral arteries. 23 Thus, in this population of subjects with a mean age of years, measured brachial PP is an acceptable approximation of PP in central (carotid) arteries. Regarding C/IF plaques, some limitations of the study need to be addressed. If arterial calcification is an agreed marker of plaques, CCA-IMT over 1 mm is a definition that differs among authors. 2,5,6 Bots et al 24 suggested that certain degrees of carotid intima media thickening appear to reflect an adaptive response, whereas, beyond a certain limit, CCA- IMT increases more rapidly than lumen diameter, revealing atherosclerotic development. In the Rotterdam study, 25 this limit was considered to occur beyond an IMT of mm. In the present study, only four patients had a nonfocal CCA-IMT measurement over 1.00 mm. Focal CCA-IMT values beyond 1.00 mm were classified as carotid plaques, without discriminating between ultrasonic plaques and intima media thickening. It should be noted that our primary goal was to use a previously defined cutoff, in keeping with other studies conducted in France on cardiovascular risk factors, such as the Vascular Aging Study (EVA) cohort. 5 Moreover, studying different CCA-IMT cutoff values as a marker of plaque, the EVA study showed no difference in the association with a familial history of coronary heart disease. 5 Finally, our distinction between CCA-IMT and plaques may be important to consider in clinical practice since, although it is not possible to differentiate between the intima and media in the observed changes in CCA wall thickness, the presence of plaques necessarily implies the presence of CCA intimal changes. Interpretation of results In subjects with untreated hypertension, recent studies have shown a positive and significant cross-sectional association between brachial PP and carotid IMT, 6,25,26 and the 4-year longitudinal EVA study 12 even showed that changes in CCA-IMT were significantly associated with changes in brachial PP. In the present cross-sectional study, CCA- IMT was also associated with high PP, whatever the adequacy of SBP and DBP control; the validity of the results was confirmed by multiple stepwise regression analysis showing a significant association of CCA-IMT with only two main variables, namely age and PP. 27,28 These findings suggest a cause effect relationship between PP and CCA-IMT. However, most studies of changes in PP vs changes in CCA-IMT on antihypertensive drug therapy indicate slight or inconsistent reductions of wall thickness in musculoelastic 29,30 but not in muscular 31 arteries. In particular, the CCA-IMT reduction obtained with antihypertensive drug therapy was substantially less than that obtained with lipid-lowering agents. 30 Moreover, most long-term studies relating BP to CCA-IMT on antihypertensive agents have shown that changes in CCA-IMT should not be evaluated in absolute values, but rather in terms of lesser progression of wall thickness with time. 32 Thus, it is safe to assume that the significant association we observed between PP and CCA-IMT does not reflect a direct cause effect relationship but rather the presence of a common denominator increasing arterial wall thickness and arterial stiffness. The mechanism of the increased PP that we observed in our four-group classification must be interpreted with care. Table 2 clearly shows that, 329

6 330 whereas the high PP in controlled hypertensive subjects was solely due to a reduction in DBP, the high PP in uncontrolled hypertensive subjects was due to both an increased SBP and a reduction in DBP, resulting in significant interactions between SBP and PP. These two different haemodynamic patterns cannot solely be explained by increased cardiac function and ventricular ejection, but also requires altered CCA stiffness and/or wave reflections. In cohorts of subjects with hypertension and atherosclerosis, this interpretation seems plausible, because increased aortic and CCA stiffness are positively and independently associated with increased CCA-IMT. 33 These findings suggest that the significant association between CCA-IMT and PP reflects intrinsic alterations of the arterial wall, involving not only a change in the geometry of carotid vessels (increased CCA-IMT) but also an accumulation of rigid material (collagen, calcifications) within the CCA wall In subjects with hypertension and end-stage renal disease, we have previously shown that the stiffness of carotid wall material, contrary to increased CCA-IMT, was a significant predictor of cardiovascular mortality. 37 An important finding in this study was that the observed changes in CCA-IMT had no substantial statistical link with the traditional antihypertensive drug therapy given to our hypertensive population. This clearly indicates that conventional drug treatment, with the exception of drugs inhibiting the renin angiotensin system, has little impact on CCA structure and function and does not restore a normal arterial wall composition. 34,38 In fact, in large cohorts of hypertensive subjects, both increased PP and aortic stiffness are the most significant independent predictors of cardiovascular risk. 10 It has recently been shown that, independent of BP reduction, normalization of arterial stiffness by appropriate drug treatment independently improves cardiovascular mortality in hypertensive subjects with end-stage renal disease. 39 In contrast to CCA-IMT, C/IF plaques were observed independently of BP control and/or PP values. Multiple regression analysis indicated that C/IF plaques were mainly influenced by wellestablished modulators of plaque progression, such as smoking, uncontrolled diabetes mellitus, and dyslipidaemia, but not by PP as an indirect marker of arterial stiffness. These findings suggest that the prevention of plaque progression could differ from the prevention of increased PP and of intima media thickening. However, these three alterations may be associated, as in subjects with diffuse atherosclerosis, in whom calcifications are accompanied by low DBP, near-normal SBP, and high PP. 26,35 The elevated incidence of uncontrolled cardiovascular risk factors such as smoking, diabetes and dyslipidaemia in our study (Table 3) suggests that their treatment may have a supplementary and specific impact on the cardiovascular risk through atherosclerotic plaque prevention. In conclusion, this study of a cohort of older subjects with essential hypertension suggests that C/IF plaques should be considered as markers of atherosclerotic development. They, therefore, call for an intensification of lipid-lowering therapy, normalization of plasma glucose, and reduction of tobacco consumption. In contrast, the independent association between CCA-IMT and PP, which was observed even in subjects with effective standard antihypertensive drug therapy, suggests that new treatment approaches aimed at decreasing PP might further reduce the cardiovascular risk. 38,39 Acknowledgements This study was supported by INSERM, Association Claude Bernard and GPH-CV. We thank Ms Anne SAFAR for her skilful technical assistance. References 1 Alan PL, Moiwbray PI, Lee AJ, Fowkes GR. Relationship between carotid intima media thickness and symptomatic and asymptomatic peripheral arterial disease The Edinburgh Artery Study. Stroke 1997; 28: Burke GL et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults The Atherosclerotic Risk in Communities (ARIC) Study. Stroke 1995; 26: Baldassare D et al. Carotid artery intima media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerosis risk factors. Stroke 2000; 31: Mannami T et al. Prevalence of asymptomatic carotid atherosclerostic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese city. The SUITA Study. Stroke 1997; 28: Zureik M et al. Differential association of common carotid intima media thickness and carotid atherosclerosis plaques with parental history of death from coronary heart disease The EVA Study. Arterioscler Thromb Vasc Biol 1999; 19: Zanchetti A et al, and 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: O Leary DH et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: Wilson PWF et al. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 2001; 103: Benetos A et al. Pulse pressure: a predictor of longterm cardiovascular mortality in a French male population. Hypertension 1997; 30: Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens 2001; 10:

7 11 Zanchetti A et al. and on behalf of the HOT Study Group. Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. J Hypertens 2001; 19: Zureik M et al. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima media thickness in a general population. The EVA study. Stroke 1999; 30: Christesen KL. Reducing pulse pressure in hypertension may normalize small artery structure. Hypertension 1991; 18: Baumbach GL. Is pulse pressure a stimulus for altered vascular structure in chronic hypertension. Hypertension 1991; 18: Tartière JM et al. Carotid intima media thickness and carotid and/or iliofemoral plaques: comparison of two markers of cardiovascular risk in hypertensive patients. J Hypertens 2003; 21: Gotto AM. Cholesterol management in theory and practice. Circulation 1997; 96: Madhavan S, Ooi WL, Cohen H, Alderman MH. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994; 23: Fang J, Madhavan S, Cohen H, Alderman MH. Measures of blood pressure and myocardial infarction in treated hypertensive patients. J Hypertens 1995; 13: Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low-density cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: Touboul JP et al. Use of monitoring software to improve the measurements of carotid wall thickness by B-mode imaging. J Hypertens 1992; 10 (Suppl 5): S37 S Pignoli P et al. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986; 74: Hintze JL. Number Cruncher Statistical System. In User Manual. Statistical Solutions Limited: Ireland, Safar ME, London GM, Asmar R, Frohlich ED. Recent advances on large arteries in hypertension. Hypertension 1998; 32: Bots ML, Hofman A, Grobbee DE. Increased common carotid intima-thickness: adaptative response or a reflection of atherosclerosis? Finding from the Rotterdam study. Stroke 1997; 28: Bots ML et al. Common carotid intima media thickness and risk of stroke and myocardial infarction The Rotterdam study. Circulation 1997; 96: Witteman JC et al. J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis. Lancet 1994; 343: Suurküla M et al. on behalf of the RIS intervention study (RIS) Group. Ultrasound evaluation of atherosclerotic manifestations in the carotid artery in highrisk hypertensive patients. Arterioscler Thromb 1994; 14: Heiss G et al. and ARIC investigators. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardio-vascular risk factors in the ARIC study. Am J Epidemiol 1991; 134: Boutouyrie P et al. Local pulse pressure and regression of arterial wall hypertrophy during long-term antihypertensive treatment. Circulation 2000; 101: Topouchian J et al. Changes in arterial structure and function under trandolapril verapamil combination in hypertension. Stroke 1999; 30: Girerd X et al. Regression of radial artery wall hypertrophy and improvement of carotid artery compliance after long term antihypertensive treatment in elderly patients. J Am Coll Cardiol 1998; 31: Simon AC, Gariepy J, Moyse D, Levenson JA. Different effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation 2001; 29: Van Popele NM et al. Association between arterial stiffness and atherosclerosis. The Rotterdam Study. Stroke 2001; 32: Safar ME, Blacher J, Mourad JJ, London GM. Stiffness of carotid artery wall material and blood pressure in humans. Stroke 2000; 31: Blacher J et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001; 38: Simons PCG et al. for the SMART Study Group. Common carotid intima media thickness and arterial stiffness Indicators of cardiovascular risk in highrisk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation 1999; 100: Blacher J et al. Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease. Hypertension 1998; 32: Safar ME. Epidemiological findings imply that goals for drug treatment of hypertension need to be revised. Circulation 2001; 103: Guerin AP et al. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 2001; 103: