Associations of blood pressure with carotid intima-media thickness in elderly Finns with diabetes mellitus or impaired glucose tolerance

(2003) 17, 705 711 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Associations of blood pressure with carotid intima-media thickness in elderly Finns with diabetes mellitus or impaired glucose tolerance U Rajala 1,3,MPäivänsalo 2, M Laakso 1,3, O Pelkonen 2, I Suramo 2 and S Keinänen- Kiukaanniemi 1,3 1 Department of Public Health Science and General Practice, University of Oulu, Oulu, Finland; 2 Department of Diagnostic Radiology, University of Oulu, Oulu, Finland; 3 Unit of General Practice, Oulu University Hospital, Oulu, Finland The aim of the present study was to evaluate the associations of ultrasonographic manifestations of carotid atherosclerosis with systolic (SBP) and diastolic blood pressure (DBP) and pulse pressure (PP) in 65- year-old Finns drawn from a population-based cohort. Carotid ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance (IGT) and 57 normoglycaemic subjects (NGT). The subjects were classified into four quartiles of SBP, DBP and PP. SBP, DBP, PP and the use of antihypertensive drugs increased along with the deterioration of glucose status. The maximal intima-media thickness (IMT) of the common carotid artery (CCA) from the lowest to the highest quartiles of SBP was 0.98 7 0.34, 1.00 7 0.35, 1.03 7 0.29, 1.18 7 0.52 mm (P ¼ 0.038), respectively. SBP was higher (161 7 22 mmhg) in the subjects with severe intimamedia thickening (maximal IMT CCA X1.2 mm) than in those with maximal IMT CCA of o1.2 mm (153 7 20 mmhg) (P ¼ 0.030). DBP and PP tended to be higher in the former than the latter group (DBP: 89 7 9 mmhg vs 86 7 9 mmhg, P ¼ 0.055 and PP: 72 7 18 mmhg vs 67 7 17 mmhg, P ¼ 0.159). The prevalence of severe intima-media thickening was 39% in the subjects in the highest SBP quartile (X170 mmhg) and 20% in the subjects with lower SBP (P ¼ 0.008). In multiple regression analysis, the adjusted OR for severe intima-media thickening was 2.9 (95% CI 1.1 7.9) in the subjects in the highest SBP quartile compared to the subjects with lower SBP. In the present study, high SBP was associated with severe carotid intima-media thickening. We suggest that the results can be generalized to apply to elderly Finnish subjects with DM and IGT, but not to normoglycaemic subjects, on the basis of this study. (2003) 17, 705 711. doi:10.1038/sj.jhh.1001594 Keywords: systolic blood pressure; intima-media thickening; carotid artery; diabetes mellitus; impaired glucose tolerance Introduction Hypertension plays an important role in the development of atherosclerosis, and the two processes have been suggested to have a common underlying mechanism. 1,2 According to several prospective population studies, systolic hypertension may be a more important cardiovascular risk factor than diastolic hypertension. 3 10 Systolic blood pressure (SBP) level rises progressively with age as a result of increasing arterial Correspondence: Dr U Rajala, Department of Public Health Science and General Practice, University of Oulu, Aapistie 1, 90220 Oulu, Finland. E-mail: urajala@cc.oulu.fi Received 3 March 2003; revised 15 May 2003; accepted 26 May 2003 stiffness. 4,8,11,12 Diastolic blood pressure (DBP) peaks earlier and declines after the age of 55 years in men and 60 years in women. As a consequence, pulse pressure (PP), that is, the difference between SBP and DBP, increases with age. 8 Some recent epidemiological studies have reported that elevated PP predicts cardiovascular disease and mortality in middle-aged and elderly adults. 7 9,13 16 In accordance with the above-mentioned facts, some cross-sectional 17 21 and prospective 22 studies have shown that SBP may be a more important risk factor than DBP for early atherosclerotic manifestations, including carotid intima-media thickening. Also, PP has been associated with the carotid intima-media thickness (IMT) in cross-sectional studies, 17,20,23 and it has predicted the progression of carotid IMT in some prospective studies. 22,23

706 We carried out a population-based study on the determinants of ultrasonographic manifestations of carotid atherosclerosis in northern Finland. Recently, we reported that the maximal intima-media thickness of the common carotid artery (CCA) measured by ultrasound correlated inversely with insulin sensitivity measured by QUICKI, and that subjects in the two lowest QUICKI tertiles had a fivefold risk for severe intima-media thickening (maximal IMT of the CCA X1.2 mm), compared to those in the highest QUICKI tertile. 24 In the present paper, we highlight the associations of carotid atherosclerosis with SBP, DBP and PP. Materials and methods In 1990 1992, a population-based study was carried out in northern Finland to assess the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT). 25 All the 1008 subjects born in 1935 and living in Oulu, a city of 100 000 inhabitants, on 1 October 1990, were invited to participate in the study. Altogether, 768 subjects attended the OGTTs, and the participation rate was 78%. In 1994 and 1996 1998, two follow-up studies were carried out. 24,26,27 OGTTs were performed at these followup visits. Questionnaires, interviews, clinical examinations and laboratory tests were used to collect data during the follow-up study in 1996 1998. Self-reported use of antihypertensive medication was recorded in the questionnaire, and 44% (91/208) of the present study subjects used some antihypertensive medication. b-blockers were the most common drugs. The use of diuretics, calcium channel blockers and ACE inhibitors was less frequent than that of b-blockers. Four measurements of blood pressure were made by the physician from both arms and in sitting and recumbent positions. The mean value of these four measurements was used in the analyses. The subjects were classified into four quartiles of SBP defined as p140, 141 153, 154 169 and X170 mmhg, into four quartiles of DBP defined as p81, 82 87, 88 92 and X93 mmhg, and into four quartiles of PP defined as p56, 57 66, 67 78 and X79 mmhg. A standardized 75-g OGTT was performed according to the instructions of the WHO Study Group. 28 After a fast of 10 12 h, a venous blood sample was drawn at 0800 1000 to obtain a fasting glucose value and values for fasting immunoreactive insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides. After that, a 75-g glucose load was given to the participants. At 2 h, a venous sample was collected for the 2-h glucose value. The concentration of blood glucose was determined with the hexokinase-glucose-6-phosphate dehydrogenase method (Merck Diagnostica, Darmstadt, Germany). The coefficients of variation (CV) for within-run studies were between 1.7 and 2.8%, depending on the glucose concentration. For day-to-day studies, the CV was 2.8% at the upper end of the reference range. Serum immunoreactive insulin concentration was measured by radioimmunoassay using the Phadeseph Insulin RIA100 kit (Pharmacia Diagnostics AB, Uppsala, Sweden), which also detects proinsulin and proinsulin conversion products with considerable sensitivity. The crossreactivity of proinsulin in this assay is about 41%. Insulin levels were not analysed from the samples of the diabetic patients with insulin treatment. To measure insulin sensitivity, a novel quantitative insulin sensitivity check index (QUICKI) was used. 29,30 QUICKI can be determined from fasting insulin and glucose values according to the equation: QUICKI ¼ 1/[log(I 0 )+log(g 0 )], where I 0 is the fasting insulin and G 0 is the fasting glucose. Altogether, 60 subjects had clinical diabetes, defined as either diabetes diagnosed by a physician before the baseline or as two elevated blood glucose values (either fasting blood glucose values of X6.1 mmol/l or 2-h OGTT values of X11.1 mmol/l) during this study in 1992 1998. All subjects with clinical diabetes (except one with cancer) and those with IGT on the basis of the 1996 1998 OGTT results were invited to participate in the present study. In addition, for each diabetic subject, a control subject with normoglycaemic test results in OGTTs in 1992 and 1996 1998 was invited to participate. The diabetic and normoglycemic groups were matched for gender, current smoking and BMI class. The formation of the study population is presented in more detail in the previous publication. 24 Carotid ultrasonography Carotid ultrasound examinations were carried out between 15 February and 29 September 2000 at the Department of Diagnostic Radiology, Oulu University Hospital. The carotid ultrasound examination was carried out using a color Doppler ultrasound system (Toshiba PowerVision 7000 or 8000) with a scanning frequency of 9 MHz in B-mode, following the same protocol throughout, by a single trained radiologist (MP) blinded to the glucose status of the participants. Each carotid system was imaged in anterior oblique and lateral planes, transversally and longitudinally, with the subject supine and the head turned away from the examiner at an angle of 451. The examiner consistently aimed at the clearest possible image of the near and far walls of the carotid arteries. The scan head was kept perpendicular to the arterial walls and the transducer usually angled laterally, to give optimal visualization. Doppler scanning was used to identify the vessels and to evaluate flow disturbances. Each scan of the common carotid artery began just above the clavicle and was moved cephalically through the bifurcation and along both the internal and external branches as

far distally as possible. The whole scanning procedure was recorded on a Super-VHS video cassette recorder (Panasonic, Osaka, Japan). All measurements were performed about 6 months later from the video image on the monitor of the ultrasound device, using its electronic calipers. The dimensions measured were the IMT and the number of atheromatous plaques. The IMT defined as the distance between the medial adventitial interface and the luminal intimal interface, was measured on each side from the CCA, the bifurcation and the internal carotid artery at the point where each seemed thickest, avoiding sites with atheromatous plaque. The IMT was measured with the instrument s electronic calipers to the nearest 0.1 mm. The mean IMT CCA, the maximal IMT CCA and the total number of plaques in the carotid arteries on both sides were used in the analyses presented in this paper. An arbitrary cutoff point (X1.2 mm) of the maximal IMT CCA was chosen in such a way that the 27% of the population with the highest values were defined as having severe intima-media thickening. In all, 54 (92%) of the subjects with clinical diabetes, 97 (95 %) of those with IGT and 57 (97 %) of the normoglycaemic subjects underwent ultrasound measurements. Statistical methods The differences between the group means of the continuous variables were tested for significance by Student s t-test, ANOVA, Mann Whitney U-test and Kruskall Wallis test as appropriate. The dichotomized variables were compared with the w 2 test. Pearson s correlation coefficients between the variables of interest were calculated when the variables were normally distributed. In the case of nonnormally distributed variables, Spearman s correlation coefficients were used. After bivariate analyses, multiple logistic regression analyses with severe intima-media thickening as a dependent variable were performed. The variables that had been associated significantly with severe intima-media thickening in the bivariate analyses were fitted into the model, and the log likelihood statistics was used in model building. The possible interaction of blood pressure with glucose status and QUICKI with glucose status was tested by interaction terms. Since the distribution of triglycerides was skewed, the analyses were performed after logarithmic transformation. P-values lower than or equal to 0.05 were considered to be statistically significant. All the statistical analyses were performed with the SPSS for Windows software, version 10.0. Results The insulin sensitivity (QUICKI) data have been reported previously. 24 The characteristics of the study population in relation to glucose status are shown in Table 1. SBP and DBP, PP and the use of antihypertensive drugs increased with the deterioration of glucose status. Diabetic subjects had lower QUICKI than the other groups. SBP correlated with the mean IMT CCA (r ¼ 0.237, P ¼ 0.001) and the maximal IMT CCA (r ¼ 0.248, Po0.001). The correlation coefficients of both DBP and PP with the mean IMT CCA and maximal IMT CCA were also significant (DBP/mean IMT CCA: r ¼ 0.144, P ¼ 0.041; DBP/maximal IMT CCA: r ¼ 0.148, P ¼ 0.036; PP/mean IMT CCA: r ¼ 0.209, P ¼ 0.003; PP/maximal IMT CCA: r ¼ 0.221, P ¼ 0.002). SBP correlated with DBP (r ¼ 0.563, Po0.001) and PP (r ¼ 0.907, Po0.001), and the correlation coefficient 707 Table 1 Characteristics of the study population in relation to glucose status DM subjects IGT subjects NGT subjects P-value N 54 97 57 Women (%) 46 63 46 0.050 SBP (mmhg) 162 7 20 158 7 21 144 7 16 o0.001 DBP (mmhg) 89 7 9 887 9 847 8 0.020 PP (mmhg) 73 7 19 71 7 17 60 7 12 o0.001 Insulin sensitivity (QUICKI) 0.319 7 0.022 0.334 7 0.027 0.335 7 0.022 0.002 Total cholesterol (mmol/l) 5.73 7 0.88 5.91 7 1.02 5.71 7 0.89 0.322 LDL cholesterol (mmol/l) 3.61 7 0.68 3.80 7 0.91 3.65 7 0.77 0.339 HDL cholesterol (mmol/l) 1.33 7 0.40 1.40 7 0.38 1.41 7 0.40 0.432 Triglycerides (mmol/l) 1.60 1.38 1.33 0.089 (0.58 5.75) (0.49 5.95) (0.56 4.70) Use of antihypertensive drugs (%) 67 46 30 0.001 Use of cholesterol-lowering drugs (%) 9 15 11 0.543 Lifetime smoking (%) No 52 64 46 0.155 1 25 years 31 19 35 X26 years 17 17 19 Data represent n, mean 7 s.d. or percentage, except for fasting triglycerides, which represent median (range).

708 between DBP and PP was also statistically significant (r ¼ 0.162, P ¼ 0.021). QUICKI correlated negatively with the maximal IMT CCA (r ¼ 0.158, P ¼ 0.027); but the correlation coefficient with the mean IMT CCA did not reach statistical significance (r ¼ 0.134, P ¼ 0.061). QUICKI did not correlate with SBP (r ¼ 0.051, P ¼ 0.486), DBP (r ¼ 0.117, P ¼ 0.110) or PP (r ¼ 0.000, P ¼ 0.995). SBP, DBP and PP were divided into quartiles, and the mean and maximal IMT CCA values were calculated (Table 2). With increasing SBP, the mean IMT CCA (P ¼ 0.043) and the maximal IMT CCA (P ¼ 0.038) increased. The differences in the mean and maximal IMT CCA values in the groups defined Table 2 Mean and maximal IMT (mm) of the common carotid arteries in relation to BP and use of antihypertensive medication Mean IMT (mm) Maximal IMT (mm) SBP (mmhg) 110 140 0.86 7 0.25 0.98 7 0.34 141 153 0.91 7 0.25 1.00 7 0.35 154 169 0.94 7 0.22 1.03 7 0.29 170 217 1.01 7 0.31 1.18 7 0.52 P=0.043 P=0.038 DBP (mmhg) 67 81 0.89 7 0.25 1.00 7 0.30 82 87 0.93 7 0.23 1.04 7 0.34 88 92 0.92 7 0.27 1.04 7 0.43 93 110 0.98 7 0.30 1.14 7 0.45 P=0.369 P=0.284 PP (mmhg) 36 56 0.86 7 0.26 0.97 7 0.34 57 66 0.95 7 0.25 1.06 7 0.34 67 78 0.95 7 0.23 1.05 7 0.32 79 125 0.96 7 0.30 1.12 7 0.52 P=0.142 P=0.274 Use of antihypertensive drugs No 0.90 7 0.23 0.99 7 0.30 Yes 0.96 7 0.28 1.10 7 0.45 P=0.145 P=0.053 Data represent mean 7 s.d. according to the DBP and PP quartiles were not statistically significant. The maximal IMT CCA tended to be higher in the subjects with self-reported use of antihypertensive drugs compared to the subjects who did not use antihypertensive medication (P ¼ 0.053). The prevalence of severe intima-media thickening was higher in men (41%) than in women (16%) (Po0.001). Its prevalence was 50% in the subjects with a long (X26 years) smoking history, 22% in the subjects who had smoked for 1 25 years and 24% in the subjects who had never smoked (P ¼ 0.004). It was 11% in the highest QUICKI tertile, 36% in the middle tertile and 33% in the lowest tertile (P ¼ 0.002). SBP was higher in the subjects with severe carotid intima-media thickening (161 7 22 mmhg) compared to those with maximal IMT CCA of o 1.2 mm (153 7 20 mmhg) (P ¼ 0.030) (Table 3). DBP tended to be higher in the former (89 7 9 mmhg) than the latter group (86 7 9 mmhg) (P ¼ 0.055). There was also a trend for PP to be higher in the former than the latter group (72 7 18 vs 67 7 17 mmhg, P ¼ 0.159). The mean QUICKI and high-density lipoprotein (HDL) cholesterol values were lower, while triglycerides were higher in the subjects with severe intima-media thickening compared to those with maximal IMT CCA of less than 1.2 mm. Instead, there was no statistically significant difference between the groups in total cholesterol and low-density lipoprotein (LDL) cholesterol. The prevalence of severe intima-media thickening was 20% in the lowest SBP quartile, 24% in the second, 22% in the third and 41% in the highest quartile (P ¼ 0.063). In all, 39% of the subjects with severe intima-media thickening were included in the highest SBP quartile (X170 mmhg), while the corresponding proportion of subjects with maximal IMT CCA o1.2 mm was 20 (P ¼ 0.008) (Table 3). The prevalence of severe intima-media thickening was not associated statistically significantly with DBP quartiles or PP quartiles. Table 3 Characteristics of the subjects with severe carotid intima-media thickening (maximal IMT CCA X1.2 mm) compared to the subjects with maximal IMT CCA of o1.2 mm Subjects with IMT of X1.2 mm (N=57) Subjects with IMT of o1.2 mm (N=151) P-value SBP (mmhg) 161 7 22 153 7 20 0.030 DBP (mmhg) 89 7 9 867 9 0.055 PP (mmhg) 72 7 18 67 7 17 0.159 Total cholesterol (mmol/l) 5.81 7 1.06 5.80 7 0.91 0.976 LDL cholesterol (mmol/l) 3.78 7 0.95 3.69 7 0.76 0.454 HDL cholesterol (mmol/l) 1.25 7 0.38 1.44 7 0.38 0.001 Triglycerides (mmol/l) 1.60 (0.76 4.47) 1.38 (0.49 5.95) 0.025 Insulin sensitivity (QUICKI) 0.323 7 0.020 0.333 7 0.027 0.004 SBP X170 mmhg (%) 39 20 0.008 DBP X93 mmhg (%) 33 21 0.073 PP X79 mmhg (%) 28 25 0.708 Data represent n, mean 7 s.d. or percentage, except for fasting triglycerides, which are median (range).

The interaction term of SBP with glucose status (P ¼ 0.591) and that of QUICKI with glucose status (P ¼ 0.264) was not statistically significant. Therefore, the multiple regression analyses were performed in the whole study population. The results of the multiple regression analyses are shown in Table 4. Two models are presented. High SBP (the highest vs the three lowest quartiles), low insulin sensitivity (the two lowest tertiles of QUICKI vs the highest tertile), male gender and long-term smoking were independently associated with severe intimamedia thickening. Adjustment by glucose status, LDL cholesterol and DBP did not change the odds ratios significantly. The adjusted odds ratio of the subjects in the highest vs the three lowest SBP tertiles (X170 vs o170 mmhg) was 2.9 (95% CI 1.1 7.9). The odds ratio for male gender was 3.6 (95% CI 1.6 8.0), that for long-term smoking was 2.8 (95% CI 1.0 7.7) and that for the subjects in the two lowest QUICKI tertiles compared to those in the highest tertile was 5.5 (95% CI 2.1 14.4). Of the study subjects, 23% had no plaques, 37% had one or two plaques and 40% had three or more plaques. The total number of plaques correlated with the mean IMT CCA (r ¼ 0.347, Po0.001) and the maximal IMT CCA (r ¼ 0.363, Po0.001). There were no statistically significant differences in the number of plaques in the groups defined according to the SBP, DBP and PP quartiles or the use of antihypertensive medication. Discussion Apart from low insulin sensitivity measured by QUICKI, the other parameters related to severe carotid intima-media thickening in the present study population were high SBP, male gender and long-term smoking. The subjects in the highest SBP quartile (X170mmHg) had a three-fold risk for Table 4 Multiple regression analysis with severe carotid intimamedia thickening (maximal IMT CCA X1.2 mm) as a dependent variable OR 95% CI Model 1 Male gender 3.3 1.5 7.2 Lifetime smoking X26 years 2.5 1.0 6.5 QUICKI (the two lowest vs the highest tertile) 4.4 1.7 11.0 SBP (the highest vs the three lowest quartiles) 3.1 1.4 7.0 Model 2 Male gender 3.6 1.6 8.0 Lifetime smoking X26 years 2.8 1.0 7.7 QUICKI (the two lowest vs the highest tertile) 5.5 2.1 14.4 SBP (the highest vs the three lowest quartiles) 2.9 1.1 7.9 Model 2 adjusted by glucose status, LDL cholesterol and DBP. SBP, the highest vs the three lowest quartiles: X170 vs o170 mmhg. severe intima-media thickening compared to those with lower SBP. We previously reported a nonsignificant increasing trend in the mean and maximal IMT of the CCA upon worsening of glucose status. 24 In prospective epidemiological studies, hypertension predisposes powerfully to coronary disease, cardiac failure, stroke and peripheral artery disease. 4 Previously, elevated DBP was thought to confer a greater cardiovascular risk than elevated SBP, which resulted in classification systems and treatment recommendations that placed a greater emphasis on the treatment of DBP. 4,8 According to several prospective population studies, however, systolic hypertension may be a more important cardiovascular risk factor than diastolic hypertension. 3 10 Support for this finding has been obtained from large intervention trials in elderly subjects, which have shown that treatment of isolated hypertension has led to a decrease in cardiovascular events. 31,32 SBP, but not DBP, has been associated with increased carotid IMT in several other populationbased studies. 17 20 Furthermore, in a large population study carried out in eastern Finland, SBP had a strong and graded association with the increase of carotid IMT in middle-aged men during a follow-up of 4 years. 22 DBP had no relationship with the IMT increase when SBP was controlled for. Intima-media thickening began to accelerate at a SBP level of approximately 120 mmhg. 22 The results of the present study, together with the previous findings, support the conclusion that systolic hypertension is a more important risk factor for carotid intimamedia thickening than diastolic hypertension. BP, especially SBP, was rather high in this study population. According to the definition of hypertension based on the current guidelines, 33,34 only 3% of the study subjects had optimal SBP (o120 mmhg) while 24% had optimal or high normal SBP (o140 mmhg). DBP was optimal (o80 mmhg) in 20% and optimal or high normal (o90 mmhg) in 62% of the study subjects. The high SBP may be partly explained by the rather high age of the population. In addition, we focused on subjects with DM and IGT. The study subjects were selected from a population-based cohort by inviting all subjects with clinical diabetes and IGT and, in addition, by selecting a normoglycaemic control subject for each diabetic subject. Of the study subjects, 73% had clinical diabetes or IGT, and high BP is obviously common in such a population. 35 The main determinants of SBP level in middleaged individuals include changes in ventricular ejection and peripheral arterial resistance. The importance of increased arterial stiffness for elevated SBP and PP increases after the age of 50 years. 11,12,36,37 The age of the present study population was rather high, and arterial stiffness possibly contributed to the high SBP. In addition, most of the study subjects had type II diabetes or IGT, and previous studies have suggested that such subjects may have stiffer vessels than subjects with normal 709

710 glucose tolerance. 38 Some studies have shown that carotid intima-media thickness and the number of plaques, as indicators of carotid atherosclerosis, associate positively with arterial stiffness. 39,40 However, there is still a debate about the temporal relationship between increased arterial stiffness and atherosclerosis. 37,39 In middle-aged and elderly adults, elevated PP has been shown to be an independent predictor of cardiovascular disease and mortality. 7 9,13 16 PP may be regarded as a manifestation of arterial stiffness in subjects over 50 years of age. 36,37 Arterial stiffness measured by pulse wave velocity has been shown to be associated with coronary artery disease 41 and to predict cardiovascular mortality. 42 We did not find a significant association between PP and severe carotid intima-media thickening, but there was a positive trend. However, the high correlation (r ¼ 0.907) between PP and SBP should be noted. We suggest that the results concerning the association of PP with carotid IMT could represent a lack of power in this study, where the differences in PP were smaller than those in SBP. In addition to the lack of power in this study, some methodological viewpoints must be considered. First, ambulatory BP monitoring has been a better predictor of cardiovascular risk than clinic BP, 42,43 which was used in this study. In addition, although PP is typically measured from the brachial artery, carotid 41 and aortic 45 (ie central) PP have been demonstrated to be more sensitive markers of coronary artery disease than brachial pressure. In conclusion, the subjects in the highest SBP quartile (X170 mmhg) had a three-fold risk for severe intima-media thickening compared to the subjects with lower SBP. DBP and PP tended to be associated with severe intima-media thickening. Of the study subjects, 73% had diabetes mellitus or IGT, and we suggest that the results can be generalized to apply to elderly subjects with DM and IGT, but not to normoglycaemic subjects. References 1 Alexander RW. Hypertension and the pathogenesis of atherosclerosis: oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension 1995; 25: 155 161. 2 Chobanian AV, Alexander RW. Exacerbation of atherosclerosis by hypertension: potential mechanisms and clinical implications. Arch Intern Med 1996; 156: 1952 1956. 3 Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. Arch Intern Med 1993; 153: 598 615. 4 Kannel W. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA 1996; 275: 1571 1576. 5 He J, Whelton PK. Elevated systolic blood pressure as a risk factor for cardiovascular and renal disease. J Hypertens 1999; 17(Suppl 2): S7 S13. 6 Antikainen R, Jousilahti P, Tuomilehto J. Systolic blood pressure, isolated systolic hypertension and risk of coronary heart disease, strokes, cardiovascular disease and all-cause mortality in the middle-aged population. J Hypertens 1998; 16: 577 583. 7 Antikainen RL, Jousilahti P, Vanhanen H, Tuomilehto J. Excess mortality associated with increased pulse pressure among middle-aged men and women is explained by high systolic blood pressure. J Hypertens 2000; 18: 417 423. 8 Kannel W. Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 2000; 85: 251 255. 9 Leonetti G, Cuspidi C, Facchini M, Stramba-Badiale M. Is systolic pressure a better target for antihypertensive treatment than diastolic pressure? J Hypertens 2000; 18(Suppl 3): S13-S20. 10 Miura K et al. Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: The Chicago Heart Association Detection Project in Industry Study. Hypertension 2001; 38: 232 237. 11 Franklin SS, Weber MA. Measuring hypertensive cardiovascular risk: the vascular overload concept. Am Heart J 1994; 128: 793 803. 12 Franklin SS et al. Hemodynamic patterns of agerelated changes in blood pressure. The Framingham Heart Study. Circulation 1997; 96: 308 315. 13 Benetos A et al. Pulse pressure: a predictor of longterm cardiovascular mortality in a French male population. Hypertension 1997; 30: 1410 1415. 14 Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension 1998; 32: 560 564. 15 Domanski MJ et al. Isolated systolic hypertension: prognostic information provided by pulse pressure. Hypertension 1999; 34: 375 380. 16 Franklin SS et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation 1999; 100: 354 360. 17 Salonen R, Salonen JT. Determinants of carotid intimamedia thickness: a population-based ultrasonography study in Eastern Finnish men. J Intern Med 1991; 229: 225 231. 18 Arnett DK et al. Hypertension and subclinical carotid artery atherosclerosis in blacks and whites: The Atherosclerosis Risk in Communities Study. Arch Intern Med 1996; 17: 1983 1989. 19 Bonithon-Kopp C et al. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries: The Vascular Aging (EVA) Study. Arterioscler Thromb Vasc Biol 1996; 16: 310 316. 20 Lassila HC et al. Prevalence and determinants of carotid atherosclerosis in healthy postmenopausal women. Stroke 1997; 28: 513 517. 21 Rantala AO et al. Hyperinsulinemia and carotid atherosclerosis in hypertensive and control subjects. Diabetes Care 1998; 21: 1188 1193. 22 Lakka TA, Salonen R, Kaplan GA, Salonen JT. Blood pressure and the progression of carotid atherosclerosis in middle-aged men. Hypertension 1999; 34: 51 56. 23 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: 550 555.

24 Rajala U et al. Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima-media thickness of the carotid artery. J Clin Endocrinol Metab 2002; 87: 5092 5097. 25 Rajala U, Keinänen-Kiukaanniemi S, Uusimäki A, Reijula K, Kivelä S.-L. Prevalence of diabetes mellitus and impaired glucose tolerance in a middle-aged Finnish population. Scand J Prim Health Care 1995; 13: 222 228. 26 Qiao Q et al. Risk for diabetes and persistent impaired glucose tolerance among middle-aged Finns. Diabetes Res Clin Pract 1996; 33: 191 198. 27 Rajala U, Qiao Q, Laakso M, Keinänen-Kiukaanniemi S. Antihypertensive drugs as predictors of Type 2 diabetes among subjects with impaired glucose tolerance. Diabetes Res Clin Pract 2000; 50: 231 239. 28 World Health Organization. Diabetes mellitus: report of a WHO Study Group. Technical Report Series No. 727. Geneva: World Health Organization, 1985. 29 Katz A et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000; 85: 2402 2410. 30 Hrebicek J et al. Detection of insulin resistance by simple quantitative insulin check index OUICKI for epidemiological assessment and prevention. J Clin Endocrinol Metab 2002; 87: 144 147. 31 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255 3264. 32 Staessen JA et al., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757 764. 33 Safar ME, Cloarec-Blanchard L, London GM. Arterial alterations in hypertension with a disproportionate increase in systolic over diastolic blood pressure. J Hypertens 1996; 14(Suppl 2): S103 S110. 34 Glasser SP et al. Vascular compliance and cardiovascular disease. A risk factor or a marker? Am J Hypertens 1997; 10: 1175 1189. 35 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157: 2413 2446. 36 1999 World Health Organization International Society of Hypertension. World Health Organization International Society of Hypertension guidelines for the management of hypertension. Guidelines subcommittee. J Hypertens 1999; 17: 151 183. 37 Isomaa B et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683 689. 38 Salomaa V et al. Arterial disease/hypertension/angiotensin system: non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes: the ARIC study. Circulation 1995; 91: 1432 1443. 39 van Popele NM et al. Association between arterial stiffness and atherosclerosis: The Rotterdam study. Stroke 2001; 32: 454 460. 40 Riley WA et al. Variation of common carotid artery elasticity with intimal-medial thickness: the ARIC study: Atherosclerosis Risk in Communities. Ultrasound Med Biol 1997; 23: 157 164. 41 Waddell TK et al. Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure. Hypertension 2001; 38: 927 931. 42 Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens 2001; 10: 257 261. 43 Khattar RS et al. Prediction of coronary and cerebrovascular morbidity and mortality by direct continuous ambulatory blood pressure monitoring in essential hypertension. Circulation 1999; 100: 1071 1076. 44 Khattar RS et al. Effect of ageing on the prognostic significance of ambulatory systolic, diastolic, and pulse pressure in essential hypertension. Circulation 2001; 104: 783 789. 45 Philippe F et al. Aortic pulse pressure and extent of coronary artery disease in percutaneous transluminal coronary angioplasty candidates. Am J Hypertens 2002; 15: 672 677. 711