Association between leisure-time physical activity and arterial stiffness in adults of the ELSA-Brasil study: a mediation analysis.

OBJECTIVES: We aimed at defining the direct and the mediated pathways for the association between leisure-time physical activity (LTPA) and carotid-to-femoral pulse wave velocity (cf-PWV), and also to identify whether these effects are influenced by sex and age. METHODS: Cross-sectional data from 13 718 adults (35-74 years) were obtained at the baseline of the ELSA-Brasil study. The cf-PWV was obtained by measuring the pulse transit time and the distance traveled by the pulse between the carotid and the femoral, as well as clinical and anthropometric parameters were measured. The levels of LTPA were determined by applying the long form of the International Physical Activity Questionnaire (IPAQ). RESULTS: Classical cardiovascular risk factors were independently associated with cf-PWV. Path analysis showed that increased levels of LTPA were directly associated with lower cf-PWV in both men and women ( ß : -0.123 ±â€Š0.03 vs. 0.065 ±â€Š0.029, P for sex = 0.165), except for diabetes. Also, the mediated effect of LTPA on SBP and DBPs, heart rate, BMI, and fasting glucose, was associated with lower cf-PWV in men and women ( ß : -0.113 ±â€Š0.016 vs. -0.104 ±â€Š0.016, P for sex = 0.692), except for diabetes. When age was tested as a moderator, the direct effect did not change significantly according to participants' age, regardless of sex. However, the mediated effect increases in both men and women over 50 years. CONCLUSION: Our findings support that LTPA in adults reduces cf-PWV by acting in different ways according to age. Physical activity in older individuals improves cardiometabolic risk factors and thus mitigates the stiffening of large arteries.

Fasting Glucose, Glycated Hemoglobin, and 2h Post-load Blood Glucose Are Independently Associated With Arterial Stiffness in Diabetes: The ELSA-Brasil Study.

The association of diabetes with increased large artery stiffness is not definitively established. We aimed to describe the carotid-femoral pulse wave velocity (cf-PWV) in participants with and without diabetes and whether the cf-PWV could vary among the different laboratory-based criteria used. A cross-sectional analysis using baseline data from 13,912 adults was used. cf-PWV as well as anthropometric, biochemical, and clinical data were measured. Diabetes was defined by previous medical diagnosis, medication use, fasting glucose, an oral glucose tolerance test (GTT), or glycated hemoglobin (HbA1c). The prevalence of diabetes was 18.7%, higher in men than in women. After adjustment, participants with diabetes showed higher cf-PWV (men: 9.7 ± 1.7 vs 9.4 ± 1.7 m/s, P < .05; women: 9.4 ± 1.6 vs 9.1 ± 1.7 m/s, P < .05). We observed a progressive increase in cf-PWV as >1 laboratory-based criterion for diabetes diagnosis was reached. Also, participants with diabetes with alterations in any laboratory-based criteria had higher cf-PWV than participants without diabetes, regardless of sex. In summary, diabetes is associated with higher cf-PWV as is each laboratory-based parameter used for its diagnosis. These results support the strong consequences of glucose dysregulation on the vascular system and provide evidence to screen all parameters involved in glycemic metabolism to improve vascular health.

Association Between Triglycerides, High-Density Lipoprotein Cholesterol, and Their Ratio With the Pulse Wave Velocity in Adults From the ELSA-Brasil Study.

Atherogenic dyslipidemia is a risk factor for cardiovascular diseases. The present study aimed to evaluate the association between triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and the triglycerides to high-density lipoprotein (TG/HDL-C) ratio with carotid-femoral pulse wave velocity (cf-PWV), a marker of vascular stiffness. Anthropometric, biochemical, and clinical data from 13,732 adults were used to assess this association. Individuals within the third TG/HDL-C tertile presented worse anthropometric, biochemical, and clinical profiles as compared with the participants in the lower TG/HDL-C tertile. There was a linear association between TG, HDL-C, and TG/HDL-C ratio and cf-PWV in both men and women (stronger in women). After adjustment for confounders, lower levels of HDL-C were associated with increased cf-PWV in men (9.63 ± .02 m/s) and women (8.90 ± .03 m/s). However, TG was not significantly associated with cf-PWV after adjustment, regardless of sex. An increased TG/HDL-C ratio is associated with higher cf-PWV only in women (9.01 ± .03 m/s), but after adjustment for HDL-C levels, the association was non-significant (8.99 ± .03 m/s). These results highlight the stronger association of HDL-C with arterial stiffness, and that the association of TG/HDL-C with cf-PWV is dependent on HDL-C.

APOE polymorphism is associated with lipid profile, but not with arterial stiffness in the general population.

BACKGROUND: Cardiovascular diseases (CVD) are the main cause of death and disability in developed countries. In most cases, the progress of CVD is influenced by environmental factors and multifactorial inheritance. The purpose of this study was to investigate the association between APOE genotypes, cardiovascular risk factors, and a non-invasive measure of arterial stiffness in the Brazilian population. METHODS: A total of 1493 urban Brazilian individuals were randomly selected from the general population of the Vitoria City Metropolitan area. Genetic analysis of the APOE polymorphism was conducted by PCR-RFLP and pulse wave velocity analyzed with a noninvasive automatic device. RESULTS: Age, gender, body mass index, triglycerides, creatinine, uric acid, blood glucose, blood pressure phenotypes were no different between ε2, ε3 and ε4 alleles. The ε4 allele was associated with higher total-cholesterol (p < 0.001), LDL-C (p < 0.001), total-cholesterol/HDL-C ratio (p < 0.001), LDL/HDL-C ratio (p < 0.001), lower HDL-C values (p < 0.001) and higher risk to obesity (OR = 1.358, 95% CI = 1.019-1.811) and hyperuricemia (OR = 1.748, 95% CI = 1.170-2.611). Nevertheless, pulse wave velocity (p = 0.66) measures were no different between genotypes. The significant association between APOE genotypes and lipid levels persisted after a 5-year follow-up interval, but no interaction between time and genotype was observed for lipids longitudinal behavior. CONCLUSION: The ε4 allele of the APOE gene is associated with a worse lipid profile in the Brazilian urban population. In our relatively young sample, the observed effect of APOE genotype on lipid levels was not translated into significant effects in arterial wall stiffness.

The association between salt intake and arterial stiffness is influenced by a sex-specific mediating effect through blood pressure in normotensive adults: The ELSA-Brasil study.

High salt intake is known to increase blood pressure (BP) and also to be associated with carotid-femoral pulse wave velocity (cf-PWV). However, recent data showed a sex-specific pattern in the salt-induced rise of BP. Thus, we aimed to investigate whether the association between salt intake and arterial stiffness also has a sex-specific pattern. A total of 7755 normotensive participants with a validated 12-h overnight urine collection in which daily salt intake was estimated were included. cf-PWV, as well as clinical and anthropometric parameters, was measured. Salt intake positively correlated with cf-PWV, in which the linear regression was steeper in women than in men (0.0199 ± 0.0045 vs 0.0326 ± 0.0052 m/s per gram of salt, P < .05). cf-PWV increases over the salt quartiles in men and women. However, after adjustment for confounders, the association remained significant only for men. In the path analysis, the direct path (men: 0.048 P < .001, women: 0.029 P = .028) was higher in men while that mediated by SBP (men: 0.020 P < .001, women: 0.034 P < .001) was higher in women. We clearly demonstrated that high salt intake has a direct and independent effect increasing arterial stiffness regardless of sex. Also, the association between salt intake and arterial stiffness is more dependent on BP in normotensive women than it is in normotensive men. These results highlight the need for a sex-specific approach in the evaluation of cardiovascular risk associated with dietary habits.

Aortic Stiffness and Age With Cognitive Performance Decline in the ELSA-Brasil Cohort.

Background Increased aortic stiffness has been associated with cognitive decline and dementia, but the results are inconsistent. This study investigated the longitudinal association of aortic stiffness and age with decreased cognitive performance in 3 cognitive tests. Methods and Results This study included 6927 participants, with a mean age of 58.8 years at baseline (2008-2010), who participated in the second wave (2012-2014) of the ELSA-Brasil (Brazilian Longitudinal Study of Adult Health) (interval between visits ranging from 2-6 years). Cognitive performance was evaluated by Memory, Phonemic, and Semantic Verbal Fluency and Trail B Tests, applied at both cohort visits. Associations with the carotid-femoral pulse wave velocity and age at baseline were investigated using linear models with mixed effects after adjusting for confounders. After all the adjustments, including for systolic blood pressure, the interaction term carotid-femoral pulse wave velocity×time proved to be statistically significant for Memory and Verbal Fluency Tests, indicating that the higher carotid-femoral pulse wave velocity at baseline was associated with a faster decline in cognitive performance in these tests between waves. The interaction term age×time was statistically significant for all cognitive tests, suggesting that increasing age at baseline was also associated with a faster decline in cognitive performance between waves. Conclusions In this relatively young cohort, and after a relatively short interval, an increased aortic stiffness at baseline was associated with a sharper decline in cognitive performances in memory and verbal fluency, regardless of systolic blood pressure levels. This study also showed that the decline in cognitive performance was faster among older individuals than among younger ones at baseline.

Carotid-femoral pulse wave velocity in a healthy adult sample: The ELSA-Brasil study.

BACKGROUND: Aging declines essential physiological functions, and the vascular system is strongly affected by artery stiffening. We intended to define the age- and sex-specific reference values for carotid-to-femoral pulse wave velocity (cf-PWV) in a sample free of major risk factors. METHODS AND RESULTS: The ELSA-Brasil study enrolled 15,105 participants aged 35-74years. The healthy sample was achieved by excluding diabetics, those over the optimal and normal blood pressure levels, body mass index ≤18.5 or ≥25kg/m2, current and former smokers, and those with self-report of previous cardiovascular disease. After exclusions, the sample consisted of 2158 healthy adults (1412 women). Although cf-PWV predictors were similar between sex (age, mean arterial pressure (MAP) and heart rate), cf-PWV was higher in men (8.74±1.15 vs. 8.31±1.13m/s; adjusted for age and MAP, P<0.001) for all age intervals. When divided by MAP categories, cf-PWV was significantly higher in those which MAP ≥85mmHg, regardless of sex, and for all age intervals. Risk factors for arterial stiffening in the entire ELSA-Brasil population (n=15,105) increased by twice the age-related slope of cf-PWV growth, regardless of sex (0.0919±0.182 vs. 0.0504±0.153m/s per year for men, 0.0960±0.173 vs. 0.0606±0.139m/s per year for women). CONCLUSIONS: cf-PWV is different between men and women and even in an optimal and normal range of MAP and free of other classical risk factors for arterial stiffness, reference values for cf-PWV should take into account MAP levels. Also, the presence of major risk factors in the general population doubles the age-related rise in cf-PWV.

Racial Differences in Arterial Stiffness are Mainly Determined by Blood Pressure Levels: Results From the ELSA-Brasil Study.

BACKGROUND: Black people have a higher risk of developing hypertension and presenting higher vascular stiffening. Our aim was to investigate whether the association between race and aortic stiffness could be explained by differences in the primary risk factors. METHODS AND RESULTS: We analyzed data from 11 472 adults (mean age, 51.9±8.9; 53.8% female) self-reported as white (n=6173), brown (n=3364), or black (n=1935). Their carotid-to-femoral pulse wave velocity (cf-PWV) as well as clinical and anthropometric parameters were measured. cf-PWV was higher in blacks than in whites or browns (men: white, 9.63±1.81; brown, 9.63±1.88; black, 9.98±1.99; women: white, 8.84±1.64; brown, 9.02±1.68; black, 9.34±1.91; P<0.05). However, this difference disappeared after adjustments for age, mean arterial pressure, heart rate, waist circumference, fasting glucose, and glomerular filtration rate (men: white, 9.68±1.54; brown, 9.68±1.50; black, 9.73±1.52; women: white, 8.93±1.32; brown, 8.98±1.29; black, 9.02±1.32; P>0.05). The association between race and arterial stiffness was significant for brown and black women in the highest cf-PWV quartile, even after controlling for covariates. There were no differences in the age-related increase in cf-PWV among the racial groups after adjustment, confirming the strong effect of age and mean arterial pressure on cf-PWV revealed by the multiple linear regression. CONCLUSIONS: Racial differences in cf-PWV were mainly attributed to differences in mean arterial pressure and age, although they cannot fully explain the association between race and cf-PWV in women in the highest cf-PWV values. This suggests that therapeutic approaches to overcome the effects of aging on the vascular system should focus on blood pressure control, especially in the black population.

Stiffness of the large arteries in individuals with and without Down syndrome.

BACKGROUND: Down syndrome is known to cause premature aging in several organ systems. However, it remains unclear whether this aging effect also affects the structure and function of the large arterial trunks. In this controlled study, the possibility of changes in the large arteries due to aging was evaluated in patients with Down syndrome. METHODS: Eighty-two subjects of both genders were selected. The Down syndrome group had 41 active subjects consisting of 19 males and 22 females (mean age 21 ± 1, range 13-42 years) without cardiovascular complications and who did not use vasoactive drugs. The control group consisted of 41 healthy individuals without trisomy 21 of the same gender and age as the Down syndrome group and who did not use vasoactive medication. Carotid-femoral pulse wave velocity was obtained as an index of aortic stiffness using an automatic noninvasive method. RESULTS: Individuals with Down syndrome had significantly lower blood pressure than those in the control group. Systolic blood pressure for the Down syndrome group and control group was 106 ± 2 mmHg vs 117 ± 2 mmHg (P < 0.001), respectively; diastolic blood pressure was 66 ± 2 mmHg vs 77 ± 2 mmHg (P < 0.001); and mean arterial pressure was 80 ± 1 mmHg vs 90 ± 1 mmHg (P < 0.001). Only age and systolic blood pressure were shown to correlate significantly with pulse wave velocity, but the slopes of the linear regression curves of these two variables showed no significant difference between the two study groups. Pulse wave velocity, which was initially significantly lower in the Down syndrome group (7.51 ± 0.14 m/s vs 7.84 ± 0.12 m/s; P <0.05), was similar between the groups after systolic blood pressure adjustment (7.62 ± 0.13 m/s vs 7.73 ± 0.13 m/s). CONCLUSION: Despite evidence in the literature that patients with Down syndrome undergo early aging, this process does not seem to affect the large arterial trunks, given that values of carotid-femoral pulse wave velocity were similar in individuals with or without trisomy 21. Considering that Down syndrome presents with chronic hypotension, it is reasonable to propose that the prolonged reduction of arterial distending pressure may contribute to functional preservation of the arteries in patients with Down syndrome.

Respective contribution of age, mean arterial pressure, and body weight on central arterial distensibility in SHR.

In spontaneously hypertensive rats (SHR), carotid and aortic distensibilities measured at operational blood pressure (BP) are reduced. Increased body weight and mean arterial pressure (MAP) are both known to reduce distensibility independently. However, whether, after adjustment to body weight and mean BP, distensibility remains reduced in SHR has never been investigated. Carotid and abdominal aorta distensibilities were measured under anesthesia in SHR at 5, 12, 52, and 78 wk of age, and measurements were compared with age-matched normotensive Wistar rats. Each age group was composed of 9 or 10 animals. We determined distensibility using echo-tracking techniques of high resolution. Compared with Wistar rats, carotid and aortic distensibilities measured at operational MAP are reduced in SHR. This reduction is accentuated with age, particularly for the carotid artery. After adjustment to body weight and MAP, carotid and aortic distensibilities become identical in Wistar and SHR (or even slightly increased in SHR) but continue to be reduced with age, mainly for the carotid artery. In conclusion, in SHR, age and high BP do not have a parallel and similar influence on the reduction of arterial distensibility. Aging constantly reduces arterial distensibility, whereas MAP levels contribute to maintenance of arterial function.

Angiotensinogen 235T allele "dosage" is associated with blood pressure phenotypes.

The genetic mechanisms underlying interindividual blood pressure variation among humans may reflect, at least in part, clustering of functional gene variants belonging to complex blood pressure control systems. In this study, we investigated the association of specific functional gene variants of the renin-angiotensin system, ACE (I/D) and angiotensinogen (M/T) genes, with blood pressure phenotypes (systolic, mean, diastolic, and pulse pressure), in an ethnically mixed urban population in Brazil. Individuals (n=1421) were randomly selected from the general population of the Vitoria City Metropolitan area. Neither gender, age, smoking status, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, or diabetes was associated with ACE or AGT polymorphism in univariate analysis. No association was found between ACE variants and blood pressure phenotypes. However, a statistically significant association was revealed between the AGT 235T variant and all blood pressure phenotypes, consistent with an additive/codominant mode of action even after adjustment for age and gender (P<0.01). Genotypic analysis contemplating both ACE and AGT variants in the same model did not show any significant interaction between both genetic polymorphisms. In addition, the AGT 235T allele was significantly associated with hypertension in a recessive model, which remained as an independent risk factor for hypertension even after adjustment for age, gender, and ethnicity (OR, 1.33; 95% CI, 1.04 to 1.70). Taken together, these data indicate a linear relation between AGT 235T allele number ("dosage") and blood pressure in an ethnically mixed urban population and confirmed its role as an independent risk factor for hypertension for men and women when in homozygosity.

NPHS2 R229Q functional variant is associated with microalbuminuria in the general population.

BACKGROUND: Microalbuminuria is a risk factor for developing end-stage renal disease and cardiovascular events. Mutations in NPHS2 have been shown to cause autosomal-recessive nephrotic syndrome. Recently, a functional polymorphism of this gene (R229Q) was described and associated with a maturity-onset form of nephrotic syndrome. We have investigated whether the carrier status of this novel genetic variant is associated with microalbuminuria in individuals from the general population. METHODS: Demographic, cardiovascular risk factors, and renal phenotypes in 1577 individuals from a cross-sectional-based study were collected following the general guidelines of the WHO-MONICA project (monitoring trends and determinants in cardiovascular diseases). Blood and urine samples were obtained. Microalbuminuria was determined using a semiquantitative protocol, and DNA was extracted from peripheral lymphocytes. RESULTS: A strong association was found between the 229Q allele and microalbuminuria (P= 0.008). The presence of the 229Q allele was still associated with a 2.77-fold increased risk of presenting microalbuminuria even after adjustment for age, ethnicity, hypertension, obesity, and diabetes in a multiple logistic regression model. In addition, a statistically significant interaction was identified between the presence of the 229Q allele and body mass index (BMI) (P= 0.01), suggesting an additive effect between the 229Q allele and other risk factors for microalbuminuria. CONCLUSION: These data have important implications for the understanding of microalbuminuria in the general population and may contribute to better ways of disease prediction and prevention.

Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population.

We investigated the association of beta2 adrenoceptor functional gene variants (Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms), obesity phenotypes, and blood pressure levels in a large, ethnically mixed urban population. The individuals (n=1576) were randomly selected for a cross-sectional study of cardiovascular risk factors in Vitória, Brazil. Statistically significant associations among systolic blood pressure and the Arg16Gly and Thr164Ile variants were identified in univariate analysis. The Gly16/Gly16 genotype was still associated with systolic blood pressure (SBP) in multivariate analysis adjusting for age, gender, ethnicity, total cholesterol, diabetes, and body mass index (BMI) (P=0.01). The Arg16 allele was the only genotypic variable associated with BMI, and, in a dominant model, it remained associated with an increased BMI even after adjustment for age, gender, ethnicity, triglycerides, HDL cholesterol, LDL cholesterol, diabetes, and hypertension status (P=0.02). Although the different polymorphisms did not interact in the determination of SBP, a significant interaction with BMI (P=0.02), not through linkage disequilibrium, was identified between the Gln27Glu and the Thr164Ile variants. Furthermore, a significant interaction among the Arg16Gly polymorphism and BMI (P=0.036) and waist-hip ratio (P=0.003) in determining SBP was disclosed by ANOVA factorial modeling, with SBP used as the dependent variable. An interaction between the Thr164Ile polymorphism and waist-hip ratio was also identified (P=0.018). Finally, multiple logistic regression models showed a 1.48-fold increase in the risk of hypertension in individuals harboring the Gly16/Gly16 genotype and a 1.31-fold (P=0.01) and a 1.49-fold (P=0.003) increased risk of obesity in individuals harboring the Gln27/Gln27 genotype or the presence of the Arg16 allele, respectively. Taken together, these data provide evidence for a strong but complex relation between beta-adrenoceptor gene variants, hypertension, and obesity.