Pediatrics 2003 Jan;111(1):61-6
Carotid artery intimal-medial thickness and left ventricular hypertrophy in children with elevated blood pressure.
Sorof JM, Alexandrov AV, Cardwell G, Portman RJ.
Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas 77030, USA. jsorof@uth.tmc.edu
OBJECTIVES: To determine the association between carotid artery intimal-medial thickness (cIMT) and left ventricular mass index (LVMI) in children with elevated blood pressure. METHODS: Study subjects (n = 32; mean age: 13.9 +/- 2.7 years) were untreated new referrals to a pediatric hypertension clinic with confirmed elevated blood pressure. LVM was calculated from 2-dimensionally guided m-mode echocardiographic measurements of the left ventricle. LVMI was calculated as LVM (g)/height (m)2.7, and left ventricular hypertrophy (LVH) was defined as LVMI >95th percentile. Carotid artery duplex ultrasound was performed by protocol by experienced vascular sonographers who were unaware of the echocardiography results. The thickest IMT complex of the far wall of the distal common carotid artery was measured in longitudinal B-mode section using a high-resolution linear array of 8 MHz. RESULTS: The prevalence of LVH and increased cIMT was 41% and 28%, respectively. Subjects with increased cIMT had higher LVMI (46.8 g/m2.7 vs 31.4 g/m2.7) than those with normal cIMT. The LVH prevalence was 89% (8 of 9) among subjects with increased cIMT as compared with 22% (5 of 23) in subjects with normal cIMT. cIMT was positively correlated with body mass index (r = 0.43), interventricular septal thickness (r = 0.58), posterior wall thickness (r = 0.54), and LVMI (r = 0.54). cIMT and LVMI were positively associated after accounting for age, gender, and body mass index. CONCLUSIONS: These findings raise the possibility that carotid duplex ultrasound, by indicating the presence of early arterial wall changes, may be useful for predicting other cardiovascular sequelae in hypertensive children.
Eur J Vasc Endovasc Surg 2002 Dec;24(6):499-504
Ultrasonic analysis of plaque characteristics and intimal-medial thickness in radiation-induced atherosclerotic carotid arteries.
Cheng SW, Ting AC, Wu LL.
Department of Surgery, The University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong. wkcheng@hku.hk
OBJECTIVES: to investigate the effect of external irradiation on the morphology of atherosclerotic plaques and the intimal-medial thickness of the carotid artery. METHODS: a group of 46 patients (16 symptomatic) who had received external irradiation to the head and neck area more than five years previously and developed carotid stenosis exceeding 50%, were evaluated by duplex ultrasound. The carotid artery lumen, intimal-medial complex, and the plaque echogenicity was determined using computer digital image processing methods. Forty-six age and sex matched patients with similar degrees of non-radiation associated carotid stenosis were used as controls. RESULTS: irradiated stenotic carotid arteries had a greater intimal-medial thickness (0.96 mm vs 0.80 mm, p=0.008) and a narrower lumen (5.5 mm vs 6.6 mm, p<0.001) than the controls. The carotid plaque characteristics (gray-scale median (GSM) and heterogeneity) of the irradiated and control groups did not differ significantly. Symptomatic patients who had received external radiotherapy to the head and neck have a more echolucent plaque (mean GSM of 98) than their asymptomatic counterparts (mean GSM 114, p=0.03). Intimal-medial thickness and carotid lumen was not related to the occurrence of symptoms. CONCLUSIONS: external irradiation to the head and neck area leads to significantly increased thickness of the carotid wall and a corresponding narrowing of the lumen. There seems to be no difference in the plaque characteristics between irradiation-induced and spontaneous carotid atherosclerosis.
Am Heart J 2002 Nov;144(5):753-9
Carotid artery intimal-medial thickness: indicator of atherosclerotic burden and response to risk factor modification.
Mukherjee D, Yadav JS.
Division of Cardiology, University of Michigan, Ann Arbor, Mich, USA.
BACKGROUND: A number of studies have used B-mode ultrasound to measure carotid intimal-medial thickness as an indicator of the severity of carotid atherosclerosis. METHODS: We reviewed the available data on carotid intimal-medial thickness in defining severity of atherosclerosis, with the use of high-quality studies that addressed clinical end points. RESULTS: Data from multiple studies demonstrate a high degree of reproducibility in measurements of intimal-medial thickness. A number of agents that include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, angiotensin-converting enzyme inhibitors, and insulin sensitizers reduce carotid intimal-medial thickness and cardiovascular events, such as myocardial infarction and stroke. CONCLUSIONS: In this review article, various methods of measuring carotid intimal-medial thickness are examined and critiqued. In addition, the effects of various lifestyle modifications and therapeutic agents on intimal-medial thickness and cardiovascular end points are evaluated.
Am J Epidemiol 2002 Nov 1;156(9):871-81
Multi-ethnic study of atherosclerosis: objectives and design.
Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, Greenland P, Jacob DR Jr, Kronmal R, Liu K, Nelson JC, O'Leary D, Saad MF, Shea S, Szklo M, Tracy RP.
Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. bildd@nhlbi.nih.gov
The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality.
Circulation 2002 Oct 15;106(16):2061-6
Associations of extracranial carotid atherosclerosis progression with coronary status and risk factors in patients with and without coronary artery disease.
Crouse JR 3rd, Tang R, Espeland MA, Terry JG, Morgan T, Mercuri M.
Department of Medicine, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
BACKGROUND: Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated th eir associations with IMT progression specifically in patients with and without CAD. METHODS AND RESULTS: We used coronary angiography to identify 280 patients equally divided between men and women and those with either > or =50% coronary artery stenosis or no CAD. Risk factors were measured at baseline and IMT was measured at baseline and yearly for 3 years in 241 of these individuals. Baseline risk factors and CAD status were related to IMT progression. IMT of patients with CAD progressed 3 times faster than that of patients with no CAD (mean+/-SEM, 33.7+/-7.4 versus 8.9+/-7.1 microm/year; P=0.02), and CAD status and high-density lipoprotein (HDL) cholesterol were independently associated with IMT progression. Male sex, increased waist to hip ratio, cig arette smoking, increased triglycerides, and decreased HDL cholesterol were associated with increased progression in CAD patients. CONCLUSIONS: Patients with CAD have more rapid progression of IMT than CAD-free controls, and risk factors are related to pr ogression in them.
Arterioscler Thromb Vasc Biol 2002 Oct 1;22(10):1698-703
Heritability of carotid artery structure and function: the Strong Heart Family Study.
North KE, MacCluer JW, Devereux RB, Howard BV, Welty TK, Best LG, Lee ET, Fabsitz RR, Roman MJ; Strong Heart Family Study.
Department of Epidemiology, University of North Carolina, Chapel Hill, USA.
OBJECTIVE: Alterations in carotid artery structure and function may represent phenotypic measures of vascular disease that contain information beyond that which can be inferred from conventional cardiovascular disease risk assessment. However, apart from their associations with cardiovascular disease risk factors and outcome, the genetic basis of variations in carotid artery structure and function is largely unknown. The purpose of this study was to examine the genetic and environmental contributions to c arotid artery structure and function in 3 large groups of American Indians. METHODS AND RESULTS: Approximately 950 men and women, aged > or =18 years, in 32 extended families were examined between 1997 and 1999. By use of a variance component approach and the program Sequential Oligogenic Linkage Analysis Routines, heritabilities for carotid artery structure and function phenotypes were estimated. After accounting for the effects of covariates (sex, age, diabetes, impaired glucose tolerance, smoking, chol esterol, body surface area, and hypertension), we detected significant heritabilities (given as h2 values) for common carotid artery diastolic diameter (h2<0.44), intimal-medial wall thickness (h2<0.21), vascular mass (h2<0.27), arterial stiffness (h2<0.2 3), and the augmentation index (h2<0.18). CONCLUSIONS: These results suggest that the additive effects of genes explain a moderate proportion of the variability of carotid artery structure and function.
Arterioscler Thromb Vasc Biol 2002 Oct 1;22(10):1692-7
Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart disease: HERS B-mode substudy.
Byington RP, Furberg CD, Herrington DM, Herd JA, Hunninghake D, Lowery M, Riley W, Craven T, Chaput L, Ireland CC, Applegate WB; The Heart and Estrogen/Progestin Replacement Study Research Group.
Wake Forest University School of Medicine, Winston-Salem, NC 27157-1063, USA. bbyingto@wfubmc.edu
OBJECTIVE: The Heart and Estrogen/Progestin Replacement Study (HERS) found no overall effect of estrogen plus progestin (compared with placebo) on coronary event rates in 2763 postmenopausal women with established coronary disease (mean 4.1 years of follo w-up). In addition to the events trial, a carotid ultrasound substudy was established in 1993 to be conducted concurrently to determine whether hormone therapy affects the progression of the underlying atherosclerotic process. METHODS AND RESULTS: Within the larger HERS, a subset of 362 participants underwent carotid B-mode ultrasound examinations at baseline and the end of follow-up. Progression of carotid atherosclerosis was measured as the temporal change in intimal-medial thickness (IMT). CONCLUSIONS: IMT progressed in the hormone treatment and placebo groups, although there was no statistical difference between the rates: IMT progressed 26 microm/y (95% CI 18 to 34 microm/y) in the hormone group and 31 microm/y (95% CI 21 to 40 microm/y) in the place bo group (P=0.44). There were also no significant treatment effects when the results were examined by carotid segment or were adjusted for covariates. These data support the American Heart Association recommendation that women with established coronary di sease should not initiate hormone therapy with an expectation of atherosclerotic benefit.
Eur J Endocrinol 2002 Oct;147(4):453-9
Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism.
Nuzzo V, Tauchmanova L, Fonderico F, Trotta R, Fittipaldi MR, Fontana D, Rossi R, Lombardi G, Trimarco B, Lupoli G.
Department of Molecular and Clinical Endocrinology and Oncology, University 'Federico II', Naples, Italy.
OBJECTIVE: Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still c ontroversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. DESIGN: Twen ty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged fro m 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. METHODS: Twenty-four-hour blood p ressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. RESULTS: No difference was found between the patients and controls in blood pressure profile, when the following parameters wer e considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a t rend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. CONCLUSIONS: Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular mani festation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subj ects.
Diabetes 2002 Oct;51(10):3069-76
Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the atherosclerosis risk in communities study.
Golden SH, Folsom AR, Coresh J, Sharrett AR, Szklo M, Brancati F.
Department of Medicine, the Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
The extent to which groupings of insulin resistance-related cardiovascular risk factors synergize to produce atherosclerosis beyond what is expected from their additive effects is uncertain. The objective of this study was to measure interactions among gr oupings of the features of the insulin resistance syndrome (IRS) on carotid intimal-medial thickness (IMT). This cross-sectional study used baseline data from the Atherosclerosis Risk in Communities Study on 11,790 adults aged 45-64 years without diagnose d diabetes, treated dyslipidemia, or coronary heart disease. The main outcome was carotid IMT, assessed using B-mode ultrasound. The excess carotid IMT attributable to each IRS grouping was determined using multiple linear regression models. There were 57 possible combinations of six IRS components (hypertension, hyperinsulinemia, obesity, hypertriglyceridemia, low HDL cholesterol, and hyperglycemia). In multivariate analysis, 29 of the 57 groupings were associated with excess carotid IMT. Individuals wit h all six IRS components had the greatest excess IMT compared with those without this grouping (71 micro m; 95% CI 40-102 micro m). The groupings most strongly associated with excess carotid IMT included hypertension and hypertriglyceridemia. Intervention s aimed at ameliorating the IRS may produce reductions in atherosclerotic risk beyond that predicted by treatment of individual IRS-related risk factors.
Stroke 2002 Sep;33(9):2177-81
Plasma homocysteine levels and atherosclerosis in Japan: epidemiological study by use of carotid ultrasonography.
Adachi H, Hirai Y, Fujiura Y, Matsuoka H, Satoh A, Imaizumi T.
Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan. hadac@med.kurume-u.ac.jp
BACKGROUND AND PURPOSE: We examined whether hyperhomocysteinemia is an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) in a large, randomly selected community in Japan where the dietary habit is different and the i ncidence of coronary artery disease is lower compared with those of western countries. METHODS: In 1111 cases (452 men, 659 women) aged 63+/-10 years old (range, 40 to 94 years) recruited from a population-based survey performed in 1999, we measured fasti ng plasma total homocysteine levels and performed bilateral carotid B-mode ultrasound. The participants underwent measurements of other blood chemistries (total cholesterol, HDL cholesterol, glycosylated hemoglobin A(1c), and creatinine). RESULTS: For the total population, the mean total homocysteine level was 10.9 micro mol/L. Total homocysteine levels were higher in men than in women and increased with aging. With multiple linear regression analysis after adjustments for age and sex, the most powerful d eterminant of total homocysteine levels was serum creatinine (P<0.001). With multiple stepwise regression analysis after adjustments for age, sex, and other confounding factors, total homocysteine was significantly (P<0.05) related to IMT. Furthermore, wh en mean values of IMT adjusted for age, sex, and other related factors were analyzed across total homocysteine quartiles, IMT (P<0.05) showed a significant trend as total homocysteine level increased. CONCLUSIONS: Plasma total homocysteine levels in Japan are similar to those reported in western countries. Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness in Japan as well.
Nippon Ronen Igakkai Zasshi 2002 Jul;39(4):400-3
[Non-invasive method of evaluating atherosclerosis in elderly patients]
Hashimoto M.
Department of General Internal Medicine, Kobe University School of Medicine.
Evidence has accumulated that impairment of vascular endothelial function is the initial step in the development of atherosclerosis. One important finding is the impairment of the release of the endothelium-dependent relaxing factor, which is now thought to be nitric oxide or its related substances, from endothelial cells. Flow-mediated dilatation (FMD) induced by reactive hyperemia has been know to be endothelium dependent, and this can be detected during reactive hyperemia by high-resolution ultrasound in superficial arteries. Several coronary risk factors such as hypercholesterolemia, smoking and hyperhomocysteinemia have been reported to be significantly related with decreased FMD. A non-invasive technique using B-mode ultrasonography can visualize an d assess the lumen and vessel wall of the carotid artery. We analyzed Intima-media thickness (IMT) of the right common carotid artery using this method. IMT thickening consists of both an intimal atherosclerotic process and medial hypertrophy. Since IMT i s increased in subjects with familial hypercholesterolemia and shows a progressive reduction with cholesterol-lowering treatment. IMT seems to be significantly related to the early phase of atherosclerosis. Ankle brachial pressure index and pulse wave vel ocity have been clinically applied to evaluate atherosclerosis. These methods are also introduced in this symposium.
Diabetes Care 2002 Aug;25(8):1425-31
Is insulin sensitivity a causal intermediate in the relationship between alcohol consumption and carotid atherosclerosis?: the insulin resistance and atherosclerosis study.
Cooper DE, Goff DC Jr, Bell RA, Zaccaro D, Mayer-Davis EJ, Karter AJ.
Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
OBJECTIVE: A J-shaped association has been demonstrated between alcohol consumption and atherosclerosis. Insulin resistance, also a risk factor for atherosclerosis, has been shown to have a similar J-shaped association with alcohol intake. This raises the question of whether insulin sensitivity (S(I)) is a causal intermediate in the alcohol-atherosclerosis relationship. RESEARCH DESIGN AND METHODS: The Insulin Resistance Atherosclerosis Study was a multicenter cohort study designed to investigate relation ships among S(I), risk factors for cardiovascular disease, and carotid artery atherosclerosis. Using regression analysis, we tested whether adjustment for S(I) attenuated the alcohol-atherosclerosis relationship observed at baseline. RESULTS: A J-shaped a ssociation was observed between alcohol consumption and common carotid artery intimal medial thickness. The protective aspect of the alcohol-atherosclerosis relationship was attenuated by 25% after the adjustment for S(I). However, an interaction was obse rved between alcohol consumption and glucose tolerance (GT) status. In comparison with never drinkers, all levels of alcohol consumption were associated with less atherosclerosis in participants with normal GT status. Participants with impaired GT status (but not diabetes) demonstrated a J-shaped alcohol-atherosclerosis association. All levels of alcohol consumption were associated with more atherosclerosis in participants with diabetes. CONCLUSIONS: S(I) may be a causal intermediate at protective levels of alcohol intake, but an alcohol-GT interaction precluded a definitive conclusion. Moderate alcohol consumption may increase the risk of atherosclerosis in people with diabetes. These findings contrast with previous reports and do not support current rec ommendations regarding moderate alcohol consumption in people with diabetes. More research is needed to clarify this issue.
Eur J Epidemiol 2001;17(9):855-61
Influence of hypertension and smoking as the single vascular risk factors on the intima-media thickness.
Csanyi A, Egervari A, Nagy Z.
Department of Neurology, Aladar Petz County and Teaching Hospital, Gyor, Hungary. saci@arrabonet.gyor.hu
In order to compare the extent of early carotid atherosclerosis between patients with single vascular risk factors (smoking = SMO or hypertension = HYP) and risk-free normal subjects (= HCS), we used intimal-medial wall thickness (IMT) measurements of the common carotid artery. The age- and sex-adjusted mean IMTs were significantly higher in the HYP and SMO groups than in the HCS control group (p < 0.005 and p < 0.001, respectively). The estimated yearly progression rate of IMT (average difference in IMT/ year age difference) was significantly higher in the HYP and SMO groups than in the HCS group (p < 0.05). In the total group, the age, hypertension, smoking and sex accounted for 52% of the variability of IMT. Our results show that the estimated yearly pr ogression rate of IMT is slower in healthy and risk-free volunteers than previously detected and that the smoking and hypertension have a similar effect to the progression of early atherosclerosis. This also emphasises the influence of smoking in initial vascular remodelling process.
J Cardiovasc Risk 2002 Apr;9(2):97-103
C-reactive protein and carotid intimal medial thickness in a community population.
Sitzer M, Markus HS, Mendall MA, Liehr R, Knorr U, Steinmetz H.
Department of Neurology, J.W. Goethe-University Frankfurt am Main, Germany, St George's Hospital Medical School, London, UK. sitzer@em.uni-franfurt.de
BACKGROUND: C-reactive protein (CRP) has been linked to cardiovascular disease and atherosclerosis. Large-scale epidemiological studies have shown a correlation of CRP level with risk of stroke, myocardial infarction and peripheral arterial disease. Never theless, the question whether serum CRP itself is an independent indicator of the atherosclerotic process remains unanswered. METHODS: In a community-based sample free of advanced atherosclerotic disease (n = 1018; mean age +/- SD, 54.1 +/- 12.0 years; 49 .7% women) we examined the relationship between carotid intimal medial thickness (IMT), conventional vascular risk factors (that is, smoking, obesity, elevated blood pressure, diabetes mellitus, hypercholesterolaemia) and serum CRP. RESULTS: We found an a ssociation between increasing IMT values with increasing CRP values for all sites within the carotid system (for example, common carotid artery [CCA-] IMT, beta = 0.174, P < 0.001). The relationship was weakened after accounting for the above-mentioned co nventional risk factors (linear regression), particularly body mass index, but remained significant (for example, mean CCA-IMT beta = 0.02, P = 0.042). Including fibrinogen in the regression made the relationship no longer significant (mean CCA-IMT beta = 0.01, P = 0.277). CONCLUSION: It is unlikely that CRP per se is a major independent cause of early arteriosclerosis. Elevations of CRP, or less specifically chronic inflammation, may mediate the effect of certain conventional risk factors on promoting at herogenesis, especially obesity.
Ann Epidemiol 2002 May;12(4):228-36
Hyperhomocyst(e)inemia and hemostatic factors: the atherosclerosis risk in communities study.
Schreiner PJ, Wu KK, Malinow MR, Stinson VL, Szklo M, Nieto FJ, Heiss G.
Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN 55454-1015, USA. schreiner@epivax.epi.umn.edu
PURPOSE: To determine whether homocyst(e)ine (H(e)) is related to hemostatic factors in a population-based sample without evidence of cardiovascular disease. METHODS: A subsample of 660 participants--67 African-American women, 53 African-American men, 201 white women, and 339 white men--was selected from the Atherosclerosis Risk in Communities Study baseline cohort. This was based on carotid intimal-medial wall thickness above the 90th percentile or below the 75th percentile of the population distribution , assessed by B-mode ultrasonography. Unadjusted and multivariable-adjusted associations between fasting plasma H(e) and the hemostatic factors fibrinogen, factor VII:c, factor VIII:c, protein C antigen, hematocrit, platelet count, beta-thromboglobulin (b eta-TG), tissue plasminogen activator (tPA), PAI-1, D-dimer, and lipoprotein[a] were examined. RESULTS: Mean age-adjusted H(e) was positively, albeit weakly, correlated with beta-TG, tPA, hematocrit, D-dimer and PAI-1; inversely correlated with protein C; and was higher in smokers, men and African-Americans. In multivariable regression, beta-TG, tPA, and factor VII:c were positively associated with H(e), as well as age, black race, male sex, and current cigarette smoking. CONCLUSIONS: These cross-sectiona l data for a biracial group of middle-aged individuals suggest that H(e) levels falling below values consistent with homocyst(e)inemia are associated with several prothrombotic factors after adjustment for sociodemographic factors. If H(e) change is antec edent to altered hemostasis, FDA-mandated fortification of grain products with folic acid for prevention of fetal neural tube defects may lead to both reduced plasma H(e) levels and improved hemostatic profiles.
Metabolism 2002 May;51(5):539-43
Ultrasonographically assessed carotid atherosclerosis in Japanese type 2 diabetic patients: Role of nonesterified fatty acids.
Taniguchi A, Nakai Y, Fukushima M, Teramura S, Hayashi R, Hama K, Marumoto K, Watanabe T, Yoshioka I, Sakaguchi K, Kishimoto H, Matsushita K, Okumura T, Tokuyama K, Nagasaka S, Sakai M.
Division of Diabetes, Kansai-Denryoku Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka-city, Osaka 553-0003, Japan.
The aim of the present study was to evaluate the association of carotid atherosclerosis (intimal-medial thickness [IMT] in plaque-free segments and carotid stenosis in plaque segments) with serum nonesterified fatty acids (NEFA) in diabetic and nondiabeti c patients. Fifty-one nonobese nonhypertensive Japanese type 2 diabetic patients aged 38 to 83 years (60.0 +/- 1.5 years, mean +/- SEM) and 23 age-matched (60.4 +/- 2.2 years, P =.439; range, 36 to 74 years) and sex-matched nondiabetic subjects were exami ned. The duration of diabetes was 9.6 +/- 1.0 years. Body mass index (BMI), blood pressure (systolic pressure, diastolic pressure), glycosylated hemoglobin (HbA(1c)), and fasting concentrations of plasma glucose, serum lipids (triglycerides, total, and hi gh-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol) and serum NEFA were measured. Using high-resolution B-mode ultrasound scan, we measured IMT in plaque-free segments of bilateral common carotid arteries, and the mean of IMT in 2 vessels was used for the analysis. Furthermore, we calculated the degree of stenosis in plaque segments of bilateral common carotid arteries. The degree of carotid stenosis was expressed as a percentage ratio between the area of plaque and that o f the lumen using the formula (Lumen Area - Residual Lumen) x 100. Both the areas were automatically measured by the system on a frozen transverse scanning plane at the site of maximal narrowing. When 2 or more plaques were present in the vessel, only tha t causing the greatest degree of stenosis was considered for analysis. Univariate regression analyses showed that mean IMT in plaque-free segments was positively correlated with age (r =.498, P =.0004) and NEFA (r =.354, P =.0188) in type 2 diabetic patie nts. The degree of stenosis was positively correlated to age (r =.422, P =.0028), duration of diabetes (r =.313, P =.0268) and NEFA (r =.540, P =.0003) in diabetic patients. Other variables, including BMI and lipid profile, were not associated both with m ean IMT in plaque-free segments and the degree of stenosis in plaque segments in our diabetic patients. Multiple regression analyses showed that mean IMT in plaque-free segments was independently associated with age (P =.0003, F = 15.2), which explained 2 6.1% of the variability of IMT in our diabetic patients. The degree of stenosis was independently predicted by NEFA (P =.0047, F = 8.9), which explained 17.2% of the variability of the carotid stenosis in our diabetic patients. In contrast, mean IMT in pl aque-free segments was positively correlated to age in nondiabetic subjects (r =.450, P =.0347). There was, however, no relationship between the degree of stenosis and the variables, including age and NEFA, in nondiabetic subjects. These results indicate that the factors contributing to IMT in plaque-free segments and the degree of carotid stenosis in plaque segments are different in nonobese nonhypertensive Japanese type 2 diabetic patients. IMT in plaque-free segments was independently associated with a ge both in nondiabetic and diabetic subjects, whereas the serum NEFA level independently predicted the degree of stenosis in plaque segments in our diabetic patients, while not in nondiabetic subjects. Thus, NEFA is considered to be one of the new risk fa ctors responsible for the progression of carotid atherosclerosis in nonobese nonhypertensive Japanese type 2 diabetic patients. Copyright 2002, Elsevier Science (USA). All rights reserved.
Am J Epidemiol 2002 Mar 1;155(5):437-45
Endogenous postmenopausal hormones and carotid atherosclerosis: a case-control study of the atherosclerosis risk in communities cohort.
Golden SH, Maguire A, Ding J, Crouse JR, Cauley JA, Zacur H, Szklo M.
Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21205, USA. sahill@jhmi.edu.
Studies examining the relation between endogenous postmenopausal hormone levels and cardiovascular disease have yielded conflicting results. After excluding women with a history of hormone replacement therapy (HRT) use, the authors conducted a US case-con trol study in 1987-1992 comparing endogenous postmenopausal hormone levels in women with and without significant carotid atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) cohort. Atherosclerosis was assessed by using B-mode ultrasound to m easure carotid artery intimal-medial thickness (IMT). Cases (n = 182) were postmenopausal women with average IMT measurements greater-than-or-equal the 95th percentile. Controls (n = 182) were frequency matched to cases on age and ARIC center and had IMT measurements < the 75th percentile. After adjustment for cardiovascular risk factors, no association was found between the odds of atherosclerosis and increasing quartiles of estrone, dehydroepiandrosterone sulfate, or androstenedione. Compared with parti cipants in the lowest quartile of sex hormone-binding globulin (SHBG), those in the highest quartile had a significantly lower odds of atherosclerosis (odds ratio = 0.48, 95% confidence interval: 0.24, 0.97). Similarly, participants in the highest quartil e of total testosterone had a lower odds of atherosclerosis (odds ratio = 0.38, 95% confidence interval: 0.20, 0.74). The authors found higher total testosterone and SHBG to be inversely related to carotid atherosclerosis, suggesting their potential impor tance in reducing atherosclerotic risk in postmenopausal women not using HRT.
Diabetes Obes Metab 2002 Jan;4 Suppl 1:S19-25
What should the role of ACE inhibitors be in the treatment of diabetes? Lessons from HOPE and MICRO-HOPE.
Heinig RE.
University of Rochester Medical School, Rochester, New York, USA. robertheinig@viahealth.org
Experimental and clinical evidence suggest that angiotensin converting enzyme (ACE) inhibition may reduce cardiovascular (CV) risk by directly affecting endothelial dysfunction, atherosclerosis and thrombus formation. These direct effects are in addition to effects on vascular tone or pressure. The Health Outcomes and Prevention Evaluation (HOPE) study assessed the role of an ACE inhibitor ramipril in reducing CV events in 9297 patients > or = 55 years who were at high risk of CV events but did not have l eft ventricular dysfunction, heart failure, or high blood pressure at the time of study entry. In the overall HOPE population, the risk of the primary composite outcome (cardiovascular death, myocardial infarction, or stroke) was reduced by 22% (p < 0.001 ), and in patients with diabetes plus one other CV risk, it was reduced by 25% (p = 0.0004). Ramipril treatment achieved risk reduction in patients with mild renal insufficiency (serum creatinine > or = 1.4 mg/dl). Ramipril treatment did not increase adve rse events in patients with renal insufficiency. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E (SECURE) demonstrated that ramipril 10 mg significantly reduced the rate of carotid intimal medial thickening , suggesting a direct effect on atherosclerotic progression.
Metabolism 2002 Feb;51(2):255-9
Relative impact of low-density lipoprotein-cholesterol concentration and insulin resistance on carotid wall thickening in nondiabetic, normotensive volunteers.
Wang PW, Liou CW, Wang ST, Eng HL, Liu RT, Tung SC, Chien WY, Lu YC, Kuo MC, Hsieh CJ, Chen CH, Chen JF, Chu JW, Reaven GM.
Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
The relative effect of an increase in low-density lipoprotein-cholesterol (LDL-C) concentration, as compared with insulin resistance and its manifestations, on intimal medial thickening (IMT) of the common carotid artery was defined in 72 healthy men and women. Insulin-mediated glucose disposal was quantified by the insulin suppression tests, in which the height of the steady-state plasma glucose (SSPG) concentration during the last 30 minutes of a 180-minute infusion of octreotide, insulin, and glucose p rovides an estimate of insulin resistance. IMT was determined by high-resolution B-mode ultrasonography. Univariate analyses defined statistically significant correlation coefficients between IMT and LDL-C concentration (r =.25, P <.05), SSPG concentratio n (r =.32, P <.01), triglycerides (TG) (r =.25, P <.05), and high-density lipoprotein-cholesterol (HDL-C) (r = -.28, P <.05) concentrations (changes associated with insulin resistance) and ratio of waist-to-hip girth (r =.29, P <.05). When forward step-wi se linear regression analysis was used, concentrations of SSPG, LDL-C and HDL-C all emerged as independent predictors of IMT (P <.05). Furthermore, the magnitude of their relationship to IMT values was comparable. These results provide evidence that insul in resistance is as significant a predictor of degree of atherogenesis (estimated by IMT) of the common carotid artery as a high LDL-C concentration. Copyright 2002 by W.B. Saunders Company
Res Commun Mol Pathol Pharmacol 2000 Jul-Aug;108(1-2):27-37
Progression of carotid atherosclerosis and the role of endothelin in diabetic patients.
Migdalis IN, Kalogeropoulou K, Iiopoulou V, Varvarigos N, Karmaniolas KD, Mortzos G, Cordopatis P.
Department of Diabetes, NIMTS Hospital, Athens, Greece.
An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since vascular endothelium is the site of formation of several substances, we have investigated the rate of progression of carotid atherosclerosis and the contribution of endothelin (ET-1), lipid peroxides [measured as thiobarbituric acid reacting species (TBARS)] and 6-keto-Prostaglandin-F1A (6-keto-PG-F1A) at baseline and after 30-months. Fifty patients with Type 2 diabetes without evidence of macroangiop athy, hypertension, proteinuria or proliferative retinopathy, and 27 healthy, non-diabetic persons were studied. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by b-mode ultrasound. Th e IMT values was significantly increased in diabetic subjects (at baseline: 1110 +/- 310 microm, after 30 months: 1260 +/- 280 microm, p < 0.01), but not in control subjects (1100 +/- 280 microm, 1200 +/- 290 microm, respectively). At baseline time both g roups had similar levels of ET-1, TBARS and 6-keto-PG-F1A. In 30-months follow-up, the ET-1 level 8.0 pmol/l (5.8-10.7) was significantly elevated in diabetic subjects, compared with the level at baseline time 7.43 pmol/l (4.8-11.1) p < 0.01. No significa nt differences were found in the other examined parameters in the studied groups. Although insulin levels remained unchanged in the two studied groups, in 30 months follow-up, the insulin level in the diabetic subjects, 92.4 +/- 35.1 pmol/l was significan tly elevated compared with those of control subjects 76.0 +/- 31.0 pmol/l, p < 0.05. In conclusion, endothelis is the main associate of the change of IMT value over 30 months in diabetic patients, in whom the extent of atherosclerosis was significantly gr eater than in control subjects.
Res Commun Mol Pathol Pharmacol 2000 Jul-Aug;108(1-2):15-25
Plasma levels of endothelin and early carotid atherosclerosis in diabetic patients.
Migdalis IN, Kalogeropoulou K, Karmaniolas KD, Varvarigos N, Mortzos G, Cordopatis P.
Department of Diabetes, NIMTS Hospital, Athens, Greece.
An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since plasma endothelin concentrations were released from vascular endothelial cells, we have investigated the possible relationship between endothelin 1 ( ET-1) and arterial wall thickness. Ninety-eight patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 50 non-diabetic subjects were studied. After an overnight fast, blood was taken for ET-1, glucose, HbA1c, lipids, insulin and C-peptide. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by B-mode ultrasound. ET-1 levels were significantly elevated in diabetic patien ts with IMT>1100 microm, 8.3 pmol/l (5.2-12.9) compared with control subjects, 7.6 pmol/l (5.0-11.0), p<0.01 and with diabetic subjects with IMT<500 microm, 7.43 pmol/l (4.8-11.1), p<0.01. The diabetic (IMT>1100 microm) study group had also significantly higher levels of insulin, 102.8 +/- 46.4 pmol/l vs control subjects, 77.5 +/- 32.4 pmol/l, p<0.01. In diabetic subjects, no correlation was found between ET-1 and IMT with glucose, HbA1c, lipids, age or duration of diabetes, respectively. We conclude that ET-1 levels are elevated in Type 2 diabetic patients with increased IMT. Thus providing further support for the role of endothelin in atherosclerosis.
Diabetes Metab Res Rev 2001 Nov-Dec;17(6):444-7
Lack of association of insulin resistance and carotid intimal medial thickness in non-diabetic Asian Indian subjects.
Snehalatha C, Vijay V, Suresh Mohan R, Satyavani K, Sivasankari S, Megha T, Radhika S, Ramachandran A.
Diabetes Research Centre, Royapuram, Madras, India.
OBJECTIVE: Atherosclerosis is associated with insulin resistance (IR) and dyslipidaemia. Impaired glucose tolerance (IGT) is characterised by IR and is associated with a higher risk of atherosclerosis. The objective of the present study was to test whethe r early atherosclerosis indicated by intimal medial thickness (IMT) of common carotid artery (CCA) and internal carotid artery (ICA) is higher in IGT than in normoglycaemic subjects (NGT) and to look for an association of IMT with IR and dyslipidaemia. ST UDY DESIGN AND METHODS: Ninety-nine randomly selected non-diabetic subjects aged >or=35 years (48 NGT and 51 IGT) were studied. Measurements of body mass index (BMI), waist/hip ratio (WHR), blood pressure, cholesterol-total, HDL, LDL, VLDL, triglycerides (TG), lipoprotein (a), apolipoprotein-A1 (Apo A1) and apolipoprotein-B (Apo B) and ratio of Apo A1/Apo B were estimated. Insulin resistance (HOMA-IR) was calculated using the fasting plasma insulin and glucose values. IMT of CCA and ICA were measured usin g high-resolution beta-mode ultrasonography. RESULTS: Subjects with IGT and NGT were matched for BMI and WHR; HOMA-IR was higher in IGT vs NGT (7.92+/-4.2 vs 6.07+/-3.76, p = 0.028). Age-adjusted IMT values were similar in NGT and IGT (CCA 0.59+/-0.17 and 0.63+/-0.22 mm and ICA 0.44+/-0.10 and 0.45+/-0.10 mm, respectively). Further analyses were done in the total group. Multiple linear regression analyses showed that CCA-IMT was significantly associated with age and negatively associated with Apo A1/Apo B ratio. ICA-IMT was associated with age only. IMT was significantly correlated with cholesterol-total and LDL-cholesterol and apolipoproteins. It was not associated with IR. CONCLUSION: In southern Indians, IGT did not influence the IMT. Although insulin resistance was higher in IGT, it was not associated with higher IMT. Conventional risk factors such as cholesterol, LDL-cholesterol and apolipoproteins showed association with IMT in the insulin-resistant population. Copyright 2001 John Wiley & Sons, Ltd.
J Nippon Med Sch 2001 Dec;68(6):482-9
Clinical usefulness of the common carotid artery blood flow velocity ratio as measured by an ultrasonic quantitative flow measurement system: evaluation with respect to prevalence of ischemic heart disease.
Nakano H, Okazaki K, Ajiro Y, Suzuki T, Oba K.
Division of Geriatric Medicine, Nippon Medical School, Tokyo, Japan. nakano@nms.ac.jp
The present study evaluated the clinical usefulness of the measurement of common carotid artery blood flow velocity by an ultrasonic quantitative flow measurement system (QFM), and its correlation with the prevalence of ischemic heart disease (IHD). The s ubjects in this study included 287 patients (149 men and 138 women; mean age, 67.6+/-11.0 years) being treated as outpatients. Bilateral common carotid artery blood flow velocity was measured using a QFM-1100 (Hayashi Denki Co., Ltd.). The "high to low ve locity ratio" (H/L ratio) was calculated by dividing the higher value by the lower value of the velocity of the common carotid artery. In 43 of 287 patients, we used an SSA-270 ACE (Toshiba Co., Ltd) to determine the presence of plaque and measure intimal -medial thickness (IMT) in the common carotid arteries. The mean H/L ratio was 1.45, with a median value of 1.25. The patients were stratified into subgroups based on H/L ratios from 1.0 and above in 0.1 increments in order to compare the prevalence rates of IHD. The prevalence rates in groups with H/L ratios of 1.3 and greater were significantly higher than those in the group with H/L ratios less than 1.3. In logistic regression analysis, the unadjusted H/L ratio was an independent risk factor for IHD at ratios from greater than 1.1 to greater than 1.6. The age-adjusted H/L ratio was an independent risk factor for IHD at ratios from greater than 1.1 to greater than 1.4. IMT was significantly higher in patients with a H/L ratio of 1.4 or greater versus pa tients with a ratio less than 1.4 (1.154+/-0.417 mm vs. 0.421+/-0.425 mm; p<0.05). The prevalence of carotid artery plaque was also significantly higher in patients with a H/L ratio of 1.4 or greater versus patients with a ratio of less than 1.4 (76.5% vs . 38.5%; p<0.03). Therefore, determination of the carotid artery H/L ratio by means of QFM may be clinically useful in screening patients for coronary artery lesions.
Arterial distensibility and physical activity in the ARIC study.
Schmitz KH, Arnett DK, Bank A, Liao D, Evans GW, Evenson KR, Stevens J, Sorlie P, Folsom AR.
Division of Epidemiology, University of Minnesota, 1300 South 2nd St., Minneapolis, MN 55454, USA. schmitz@epi.umn.edu
PURPOSE: Arterial distensibility decreases with age. This decrease may be associated with the initiation and/or progression of hypertension and atherosclerosis and may be attenuated by positive lifestyle habits, including habitual physical activity. We te sted the hypothesis that self-reported sport, leisure, and work physical activity is associated with greater arterial distensibility (i.e., carotid artery pulsatile diameter changes). METHODS: The Atherosclerosis Risk in Communities (ARIC) study assessed left common carotid arterial diameters and intimal-medial wall thickness (IMT) using B-mode ultrasound techniques, in 10,644 African-American and white men and women aged 45-64 yr and free of cardiovascular disease. RESULTS: Work activity, but not sports or leisure activity, was weakly associated with greater arterial distensibility in an ANCOVA model adjusted for blood pressure and other covariates (diastolic arterial diameter, pulse pressure, pulse pressure squared, age, race, sex, smoking, dietary fat intake, height, education, and clinical center) (P for linear trend = 0.03). Vigorous sports activity was weakly positively associated with arterial distensibility (arterial diameter change (mean +/- SE in mm) 0.42 +/- 0.004 vs 0.41 +/- 0.002 for the 12.7 % of participants reporting any vs no vigorous activity, P = 0.02), and this association was not attenuated by adjustment for IMT, body mass index, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or diabetes. Repeate d analyses with traditional arterial stiffness indices showed similar findings for vigorous but not work activity. CONCLUSION: In contrast to several smaller studies, these findings do not support the hypothesis that habitual physical activity has a stron g, consistent positive effect on arterial distensibility.
Circulation 2001 Dec 4;104(23):2815-9
Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.
Davis PH, Dawson JD, Riley WA, Lauer RM.
Division of Cerebrovascular Diseases, Department of Neurology, University of Iowa, Iowa City, Iowa, USA. pat-davis@uiowa.edu
BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its rel ationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristic s and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diasto lic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of c arotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk fac tors, as well as risk factor load.
J Investig Med 2001 Nov;49(6):505-13
Relationship of early carotid artery disease with lipoprotein (a), apolipoprotein B, and fibrinogen in asymptomatic essential hypertensive patients and normotensive subjects.
Rossl A, Baldo-Enzi G, Ganzaroli C, Coscetti G, Calabro A, Baiocchi MR, Maiolino G, Pessina AC, Rossi GP.
Department of Internal Medicine Clinica Medica I, University of Padua, Italy.
BACKGROUND: We investigated the relationships between plasma lipids and lipoprotein fractions and carotid artery lesions (CAL) in 177 cerebro-vascularly asymptomatic subjects, of whom 107 were primary hypertensive patients and 70 normotensive controls. ME THODS: The prevalence and severity of CAL, as assessed by calculating a score of severity (score of CAL) and the maximal stenosis of both sides, as well as the intimal-medial thickness (IMT) were evaluated with a high-resolution echo-Doppler technique. We measured total serum cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lipoprotein (a) [Lp(a)], Apo (apolipoprotein)AI, ApoAII, ApoB, and fibrinogen. RESULTS: Both the prevalence (59.4% vs 26.2%) and s everity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensive patients than in controls. Regression analysis showed different predictors of IMT and maximal stenosis. The variables that remained in the model were age , mean blood pressure (BP), and smoking for IMT; pulse pressure, known duration of hypertension (HT), fibrinogen, and ApoB for the score of CAL; and the last four variables along with age and mean BP for maximal stenosis. Furthermore, we identified a link between the atherogenic lipoprotein fractions Lp(a) and ApoB, fibrinogen and early carotid artery atherosclerotic changes. CONCLUSIONS: The different correlates of IMT, CAL, and maximal degree of stenosis suggest that they reflect different events occurr ing in the arterial wall in response to aging, HT, and other risk factors, rather than simply different stages of the same atherosclerotic process.
Int J Clin Pract Suppl 2001 Jan;(117):13-8
Modifying the natural history of atherosclerosis: the SECURE trial.
Lonn E.
Hamilton Health Sciences Corporation, Hamilton General Hospital, Ontario, Canada.
Experimental and epidemiological evidence suggests that activation of the reninangiotensin-aldosterone system and oxidative modification of low density lipoprotein cholesterol both play important roles in atherosclerosis. A substudy of the HOPE (Heart Out comes Prevention Evaluation) trial, the SECURE trial (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E), evaluated the effects of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor, ramip ril, and with vitamin E on atherosclerosis progression in high risk patients. A total of 732 patients were enrolled into the study. These patients were 55 years or older, had vascular disease or diabetes with at least one other cardiovascular risk factor, but did not have heart failure or low ejection fraction. Patients were randomly assigned according to a three-by-two factorial design to receive placebo, ramipril 2.5 mg/day or ramipril 10 mg/day and placebo or vitamin E 400 IU/day. Progression of athero sclerosis was evaluated by B-mode carotid ultrasonography. The primary outcome evaluated was the annualised progression slope of the mean maximum carotid intimal-medial thickness (IMT) across 12 pre-selected carotid arterial segments. The average follow-u p was 4.5 years. The progression slope of the mean maximum IMT was 0.0217 +/- 0.04 mm/year in the placebo group, 0.018 +/- 0.44 mm/year in the ramipril 2.5 mg/day group and 0.0137 +/- 0.04 in the ramipril 10 mg/day group (P = 0.33 for the overall effect o f ramipril and P = 0.028 for the comparison between patients receiving ramipril placebo and ramipril 10 mg/day). The reduction in atherosclerotic progression observed with ramipril remained significant after adjusting for systolic and diastolic blood pres sure changes (P = 0.043) and after multivariate adjustment (P = 0.046). Administration of vitamin E 400 IU/day had no impact on atherosclerosis progression. The SECURE study is the first demonstration, in human subjects, of an effect of ACE inhibition on atherosclerotic progression. This benefit cannot be explained by the lowering of blood pressure alone. Vitamin E 400 IU/day had a neutral effect on the ultrasound measurements of atherosclerosis progression in the SECURE trial.
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