Christos Pitsavos

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

Impact of lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study

BACKGROUND Individuals with the metabolic syndrome (MS) are at high risk for coronary heart disease and may benefit from aggressive lifestyle modification. In this study, we evaluated the effect of leisure time physical activity (PA) and the Mediterranean diet (MD) on the prevalence of the MS. METHODS The ATTICA study is a health and nutritional survey. On the basis of a multistage, random sampling, 1128 men and 1154 women (>18 years old) without any evidence of cardiovascular disease or diabetes mellitus were enrolled from the greater Athens area during 2001 to 2002. The MS was defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria. PA was determined from a detailed questionnaire and graded according to the kcal/min expanded. MD was assessed through a validated nutrient questionnaire. RESULTS The overall prevalence of the MS was 453 of 2282 subjects (19.8%). Of these subjects, 284 (25.2%) were men and 169 (14.6%) were women (P <.001). The prevalence of the MS increased accordingly to age (P for trend <.001). With multiple logistic regression analysis, the odds ratio of having the MS when the participant consumed the MD was 0.81 (95% CI, 0.68-0.976), and when even a little to moderate PA (<7 kcal/min)was reported, the odds ratio was 0.75 (95% CI, 0.65-0.86). The higher levels of inflammation and coagulation markers among participants with MS did not explain much of the aforementioned effect of lifestyle modification. CONCLUSION MS is common in Greece and is becoming even more common in the middle-aged population. The suggested therapeutic lifestyle approach may contribute to the reduction of the prevalence of the MS, beyond the levels of several lipid, inflammation, and coagulation markers.

Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study

BACKGROUND Greater adherence to the Mediterranean diet has been associated with a lower incidence of cardiovascular disease and cancer. OBJECTIVE We studied the effect of the Mediterranean diet on total antioxidant capacity (TAC) in 3042 participants who had no clinical evidence of cardiovascular disease. DESIGN During 2001-2002, a random sample of 1514 men and 1528 women aged 18-89 y from the Attica area of Greece was selected. TAC was measured with an immune-diagnostic assay. Food consumption was evaluated with a validated food-frequency questionnaire, and adherence to the Mediterranean diet was assessed on the basis of a diet score that incorporated the inherent characteristics of this diet. RESULTS TAC was positively correlated with diet score. The participants in the highest tertile of the diet score had, on average, 11% higher TAC levels than did the participants in the lowest tertile, even after adjustment for relevant confounders (P < 0.01). On the other hand, the participants in the highest tertile of the diet score had, on average, 19% lower oxidized LDL-cholesterol concentrations than did the participants in the lowest tertile (P < 0.01). An additional analysis showed that TAC was positively correlated with the consumption of olive oil (rho = 0.54, P = 0.002) and of fruit and vegetables (rho = 0.34 and rho = 0.31, respectively; P < 0.001 for both), whereas it was inversely associated with the consumption of red meat (rho = -0.35, P = 0.02). CONCLUSION Greater adherence to the Mediterranean diet is associated with elevated TAC levels and low oxidized LDL-cholesterol concentrations, which may explain the beneficial role of this diet on the cardiovascular system.

Unfavorable Effect of Smoking on the Elastic Properties of the Human Aorta

BACKGROUND Smoking is a major risk factor for cardiovascular morbidity and mortality. Because previous studies have shown that smoking affects vasomotor response, we hypothesized that smoking may also acutely alter aortic elastic properties. METHODS AND RESULTS We studied 40 male current and long-term smokers who underwent diagnostic cardiac catheterization for chest-pain evaluation. Twenty subjects (age, 48 +/- 2 years, mean +/- SEM) were randomly assigned to smoking and 20 (age, 47 +/- 2 years) to sham smoking studies. Aortic elastic properties were studied with the determination of the aortic pressure-diameter relation before smoking, every minute for the first 5 minutes after the initiation of smoking or sham smoking, and every 5 minutes for the following 15 minutes. Instantaneous diameter of the thoracic aorta was measured with a special ultrasonic dimension catheter developed in our laboratory and previously validated. Instantaneous aortic pressure was measured at the same site as was diameter with a Millar micromanometer. Smoking was associated with significant changes in the aortic pressure-diameter relation that denote deterioration of the elastic properties and were maintained during the whole study period: the slope of the pressure-diameter loop became steeper (baseline, 35.43 +/- 1.38; minute 1, 45.26 +/- 1.65; peak at minute 10, 46.36 +/- 1.69 mm Hg/mm; P < .001) and aortic distensibility decreased (baseline, 2.08 +/- 0.12; minute 1, 1.60 +/- 0.08; nadir at minute 5, 1.54 +/- 0.07 x 10(-6) cm2.dyne-1; P < .001). In contrast, no changes in aortic elasticity indexes were observed with sham smoking. CONCLUSIONS Smoking is associated with an acute deterioration of aortic elastic properties. This effect of smoking may contribute to the unfavorable consequences of smoking on the cardiovascular system.

Aortic stiffness in young patients with heterozygous familial hypercholesterolemia.

BACKGROUND Dyslipidemia is a primary risk factor for the development of atherosclerosis. Aortic distensibility is an important determinant of left ventricular function and coronary blood flow whose possible alterations in patients with dyslipidemia have not been fully investigated. METHODS To assess the effect of dyslipidemia on the elastic properties of the aorta, we studied 60 patients (mean age 37+/-11 years) with heterozygous familial hypercholesterolemia and no manifest arterial disease and compared them with 20 of their normolipidemic siblings (mean age 34+/-10 years). Two indexes of the aortic elastic properties were measured: aortic distensibility was calculated by use of the formula: 2 x (AoS-AoD)/PP x AoD, and aortic stiffness index was calculated by use of the formula: In (SBP/DBP)/(AoS-AoD)/AoD, where AoS and AoD are aortic root end-systolic and end-diastolic diameters, respectively, SBP and DBP are systolic and diastolic arterial pressure, respectively, and PP is pulse pressure. Internal aortic root diameters were measured at 3 cm above the aortic valve by use of two-dimensional guided M-mode transthoracic echocardiography, and arterial pressure was measured simultaneously at the brachial artery by sphygmomanometry. RESULTS The mean aortic systolic and diastolic diameter index did not differ significantly between the two groups. In contrast, aortic distensibility was found to be significantly reduced in subjects with isolated familial hypercholesterolemia compared with that in the control group (2.15+/-1.72 cm2.dynes(-1).10(-6) vs 3.18+/-1.58 cm2.dynes(-1).10(-6), p < 0.02). In addition, the mean aortic stiffness index was double in patients with familial hypercholesterolemia compared with that in normolipidemic subjects. CONCLUSIONS Severe dyslipidemia does not overtly influence aortic dimensions but leads to impairment of aortic elastic properties before the occurrence of clinical manifestations of atherosclerotic disease.

Aortic Function in Arterial Hypertension Determined by Pressure-Diameter Relation Effects of Diltiazem

BACKGROUND Aortic elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in hypertension. The aim of this study was to determine aortic function in hypertensive patients and in normal subjects before and after administration of diltiazem, a calcium antagonist widely used in the treatment of essential hypertension. METHODS AND RESULTS The aortic pressure-diameter relation was obtained before and after diltiazem administration in 15 hypertensives and 15 control normotensives. Instantaneous diameter of the thoracic aorta was acquired with a high-fidelity intravascular catheter developed in our institution and previously validated. Instantaneous aortic pressure was measured simultaneously and at the same aortic level with a catheter-tip micromanometer. Energy loss due to the viscosity of aortic wall was measured from the area of the loop. Aortic distensibility was calculated using the formula 2 x (pulsatile change in aortic diameter)/([diastolic aortic diameter] x [aortic pulse pressure]). At baseline, aortic distensibility was lower and energy loss was greater in hypertensives than in normotensives (distensibility: 1.4+/-0.3 versus 3.5+/-0.7 cm2 x dyne(-1) x 10(-6), respectively, P<.001; energy loss: 14.1+/-3.3 versus 8.2+/-2.2 mm x mm Hg, respectively, P<.001). After diltiazem administration, aortic distensibility was increased, whereas energy loss was decreased in both hypertensives (peak response: distensibility, 2.0+/-0.4 cm2 x dyne(-1) x 10(-6), P<.001; energy loss, 9.3+/-1.6 mm x mm Hg, P<.001) and normotensives (peak response: distensibility, 5.2+/-0.5 cm2 x dyne(-1) x 10(-6), P<.001; energy loss, 5.0+/-1.2 mm x mm Hg, P<.001). CONCLUSIONS Aortic elastic properties are compromised and energy loss due to aortic wall viscosity is increased in hypertensives compared with normotensives. Function of the aorta is improved in both hypertensive and normotensive subjects after the administration of diltiazem.

Epidemiology of leisure-time physical activity in socio-demographic, lifestyle and psychological characteristics of men and women in Greece: the ATTICA Study

BackgroundWe aimed to evaluate the prevalence, frequency and type of leisure-time physical activity (LTPA) among adults in Greece, as well as its relationship with socio-demographic, lifestyle and clinical characteristics of these people.MethodsFrom May 2001 to December 2002 we randomly enrolled 1514 men and 1528 women, without any evidence of cardiovascular or any other chronic disease. The sampling was stratified by the age – gender distribution of (census 2001) of the greater area of Athens. Weekly energy expenditure assessed by considering frequency, duration (in minutes) and intensity of sports related physical activity during a usual week.Results53% of men and 48% of women were classified as physically active. Men were more likely to be active as compared to women (p < 0.05), while the lowest activity rates were observed in 40 to 49 years old participants (p < 0.01). Physically active people had higher occupation skills, were more likely to live in rural areas, to be unmarried, non smokers and they were devoted to a healthier dietary pattern, as compared to sedentary, irrespective of age and sex (all p < 0.05). In addition, the cumulative risk factors score of obesity, hypertension, hypercholesterolemia and diabetes, was inversely associated with activity status (p < 0.001). Finally, physically active men and women were less likely to report depressive symptoms (p < 0.01), after various adjustments were made.ConclusionHalf of the studied population reported physically inactive, indicating that sedentary lifestyle becomes a serious epidemic in Greece. High occupation skills, non-smoking, devotion to a healthier dietary pattern and a better cardiovascular risk factors profile were some of the determinants of physically active people.

Unsaturated fatty acids are inversely associated and n-6/n-3 ratios are positively related to inflammation and coagulation markers in plasma of apparently healthy adults.

BACKGROUND Blood lipids and inflammatory markers levels have been associated with the development and progression of atherosclerosis. As the association of inflammatory markers with plasma fatty acids has not been extensively evaluated and understood, we sought to investigate the associations between dietary and plasma fatty acids with various inflammation and coagulation markers. METHODS High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), fibrinogen, and homocysteine were measured in serum of 374 free-living, healthy men and women, randomly selected from the ATTICAs study database. Total plasma fatty acids were determined by gas chromatography. Dietary fatty acids were assessed through a semi-quantitative FFQ. RESULTS Multi-adjusted regression analyses revealed that plasma n-3 fatty acids were inversely associated with CRP, IL-6 and TNF-alpha; plasma n-6 fatty acids were inversely associated with CRP, IL-6 and fibrinogen; monounsaturated fatty acids were inversely associated with CRP and IL-6 (all p-values<0.05). Interestingly, the n-6/n-3 ratios exhibited the strongest positive correlations with all the markers studied. No associations were observed between dietary fatty acids and the investigated markers. CONCLUSIONS Measurements of total plasma fatty acids could provide insights into the relationships between diet and atherosclerotic disease. Moreover, the n-6/n-3 ratio may constitute a predictor of low-grade inflammation and coagulation.

Association of Leisure-Time Physical Activity on Inflammation Markers (C-Reactive Protein, White Cell Blood Count, Serum Amyloid A, and Fibrinogen) in Healthy Subjects (from the ATTICA Study)

T the 20th century, many researchers focused their interest on prevention and therapy of cardiovascular diseases. Among the factors that may influence the occurrence of disease is the beneficial effect of physical activity, which has been discussed in several studies.1–3 In addition, recent studies have provided evidence that inflammation plays a role in the pathogenesis of cardiovascular disease.4,5 Several investigators have addressed the association between fitness and the inflammation process,6–9 but the strength of this relation has not been fully investigated. The aim of this study is to evaluate the effect of various levels of leisure-time physical activity on inflammation markers, such as high-sensitivity C-reactive protein (CRP), fibrinogen, amyloid A, and white blood cell (WBC) counts, in a population-based sample of healthy adults. • • • The ATTICA study is a health and nutrition crosssectional survey that was carried out in the province of Attica from 2001 to 2002. A sample of 891 men and 965 women, aged 18 years old, was drawn from the general population, which excluded persons living in institutions, or subjects with mobility problems or who had chronic disease that could restrict their physical activity status (e.g., arthritis). Also, all subjects entered into this study were without any clinical evidence of coronary heart disease, stroke, or any atherosclerotic disease according to a detailed medical history, a physical examination, and electrocardiography as performed by a cardiologist. The stratification was random and based on the age/gender/city distribution of the Attica area (census of 2001). The study’s design anticipated enrolling only 1 participant per household (78% of the selected subjects participated). The number of the participants was determined by power analysis. All participants were interviewed by trained personnel who used a standard questionnaire. Physical activity was defined as any type of nonoccupational physical exercise 1 time per week, during the past year. A self-reported questionnaire was applied that was based on a special questionnaire for the assessment of leisure-time physical activity.10 Physical activity was graded in qualitative terms as follows: light (expended calories 4 kcal/min, i.e., walking slowly, stationary cycling, light stretching, and so forth), moderate (expended calories 4 to 7 kcal/min, i.e., walking briskly, cycling outdoors, swimming with moderate effort, and so forth), and high (expended calories 7 kcal/min, i.e., walking briskly uphill, long distance running, cycling fast or racing, swimming fast crawl, and so forth). The remaining subjects were defined as physically inactive. The duration of physical activity, in years of exercise, was also taken into account. Venous blood samples were collected between 8 and 10 A.M., with patients seated after 12 hours of fasting and avoidance of alcohol. High-sensitivity CRP levels, as well as fibrinogen levels, were measured by BNII Dade Behring Inc. (Leiderbach, Germany) automatic nephelometry. For the determination of plasma fibrinogen, blood was anticoagulated with 3.8% trisodium citrate (9:1 volume/volume) and cooled on ice until centrifugation. The intraand interassay coefficients of variation of fibrinogen did not exceed 9%, total cholesterol 8%). All other biochemical examinations (uric acid, urea, creatinine, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, triglycerides) were measured using a chromatographic enzymatic method with a Technicon RA-1000 automatic analyzer (TexLab Inc., Houston, Texas). Blood pressure at rest was measured with subject sitting comfortably for 5 to 10 minutes and the cuff arm supported at the heart level. Hypertension was defined as systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or the use of any antihypertensive medication. Hypercholesterolemia was defined as total cholesterol levels 220 mg/dl or the use of antilipidemic medication. Diabetes mellitus was defined as a fasting blood sugar 125 mg/dl or the use of antidiabetic medication. The questionnaire given to subjects included the following demographic characteristics: age, gender, financial status (classified as low, moderate, high, and very high), and educational level (as an index of social status) that was measured in years of schooling. DiFrom the Cardiology Clinic, School of Medicine, University of Athens; Hellenic Heart Foundation, Athens, Greece; and Cardiology Division, Georgetown University, Washington, DC. The ATTICA study is funded by research grants from the Hellenic Cardiological Society and the Hellenic Heart Foundation, Athens, Greece. Dr. Panagiotakos’ address is: 48-50 Chiou Str., Glyfada, 165 61, Attica, Greece. E-mail: D.b.Panagiotakos@usa.net. Manuscript received July 29, 2002; revised manuscript received and accepted September 24, 2002.

The associations between physical activity, inflammation, and coagulation markers, in people with metabolic syndrome: the ATTICA study:

Objective Metabolic syndrome is a condition that promotes atherosclerosis and increases the risk of cardiovascular mortality and morbidity. We evaluated whether leisure time physical activity is associated with the levels of inflammatory and coagulation markers, in people with metabolic syndrome. Methods From May 2001 to December 2002 we randomly enrolled 1514 men and 1528 women (>18 years old), without any clinical evidence of cardiovascular disease, stratified by age-gender (census 2001). The population of the study was divided into those who fulfilled the NCEP ATP III criteria for the metabolic syndrome (n = 701 or 33% men and 13% women) and the rest of the participants (n = 2341). We assessed the relationship between self-reported physical activity status and inflammatory, and coagulation markers [i.e., C-reactive protein (CRP), serum amyloid-A (SAA), interleukin (IL)-6, tumour necrosis factor (TNF)-α, white blood cell (WBC) counts, and fibrinogen (FIB)], after taking into account the effect of several confounders. Results Of the non-metabolic syndrome group, 56% of men and 58% of women were classified as sedentary, while of the metabolic syndrome group 58% men and 72% women were sedentary. After controlling for various potential confounders we found that physically active individuals with the metabolic syndrome had 36% lower levels of CRP, 15% lower levels of WBC, 19% lower levels of SAA, 15% lower levels of TNF-α, 30% lower levels of IL-6 and 15% lower levels of FIB, compared to sedentary (all P<0.05). Similar results were observed in the non-metabolic syndrome group. Conclusions The adoption of a physically active lifestyle is independently associated with lower levels of the investigated biomarkers in individuals with the metabolic syndrome. The latter may suggest a pathway for reducing cardiovascular events, even in high-risk people. Eur J Cardiovasc Prev Rehabil 12: 151–158