Non-Alcoholic Fatty Liver Disease Modifies Serum Gamma-Glutamyl Transferase in Cigarette Smokers.

BACKGROUND: Serum gamma-glutamyl transferase (GGT) is a marker of oxidative stress, associated with increased cardiovascular (CV) risk. The impact of smoking on oxidative stress may be aggravated in individuals with non-alcoholic fatty liver disease (NAFLD). We aimed to ascertain the association of smoking on GGT levels in the presence or absence of NAFLD. METHODS: We evaluated 6,354 healthy subjects (43 ± 10 years, 79% males) without clinical cardiovascular disease (CVD) undergoing an employer-sponsored physical between December 2008 and December 2010. NAFLD was diagnosed by ultrasound and participants were categorized as current or non-smokers by self report. A multivariate linear regression of the cross-sectional association between smoking and GGT was conducted based on NAFLD status. RESULTS: The prevalence of NAFLD was 36% (n = 2,299) and 564 (9%) were current smokers. Smokers had significantly higher GGT levels in the presence of NAFLD (P < 0.001). After multivariable adjustment, current smoking was associated with 4.65 IU/L higher GGT level, P < 0.001, compared to non-smokers. When stratified by NAFLD, the magnitude of this association was higher in subjects with NAFLD (ß-coefficient: 11.12; 95% confidence interval (CI): 5.76 - 16.48; P < 0.001); however, no such relationship was observed in those without NAFLD (ß: -0.02; 95% CI: -3.59, 3.56; P = 0.992). Overall the interaction of NAFLD and smoking with GGT levels as markers of oxidative stress was statistically significant. CONCLUSIONS: Smoking is independently associated with significantly increased oxidative stress as measured by GGT level. This association demonstrates effect modification by NAFLD status, suggesting that smoking may intensify CV risk in individuals with NAFLD.

Does physical activity influence the association between depressive symptoms and low-grade inflammation in adults? A study of 8,048 adults.

This study investigated whether physical activity (PA) influences the association between depression risk and low-grade inflammation. This was a cross-sectional study including 8,048 adults (18-59y). Depression symptoms were evaluated with the Beck depression inventory (BDI) and physical activity through the international physical activity questionnaire. Adults with infectious and inflammatory diseases were excluded. Blood samples were collected, including high sensitivity C-reactive protein (CRP), a marker of low-grade inflammation when ≥3mg/L. Additional measures of LDL-C, HDL-C, triglycerides and fasting glucose were also determined. Sex, chronological age, tobacco smoking, alcohol drinking, body mass index, dyslipidemia, high blood pressure and fasting glucose were used as covariates. Mediation models were conducted using the procedures of Karlson Holm Breen. Adults with elevated CRP (≥3mg/L) compared to those with low CRP (<3mg/L) presented with higher BDI scores [8.5%(95%CI:7.2%-10.1%) vs. 5.8%(95%CI:5.2-6.4)] as well as higher prevalence of physical inactivity 67.4% (95%CI:64.9-69.9) vs. 59.7% (95%CI:58.4-60.9). The prevalence of elevated CRP was highest in physically inactive adults with greater depression risk. Models revealed that physical activity risk explained 13% of the association between depression risk and elevated CRP (p=0.035), independently of potential confounders. Physical activity may reduce the association between depression symptoms and elevated CRP. Future longitudinal research is required to determine the directionality of the relationships observed.

Self-initiated changes in physical activity and incidence of Metabolic Syndrome: A longitudinal follow-up study.

AIM: The aim of this study was to analyze the association between longitudinal physical activity patterns (persistently inactive, became active, became inactive, and persistently active) and the incidence of Metabolic Syndrome (MS) among adults. METHODS: Our cohort included 5766 adults (18-59y) undergoing repeated routine health screening examinations, with a mean follow-up period of three years. Only subjects without MS at baseline were included in the study. MS was defined according to the ATP III definition, including assessments of fasting blood samples for the collection of HDL-C, triglycerides and glucose, blood pressure, and waist circumference. Physical activity was estimated using the international physical activity questionnaire and four patterns were created (persistently active, became active, became inactive, and persistently inactive). Information on tobacco smoking and alcohol consumption (through structured validated questionnaires), age, interval between baseline and follow-up, anti-hypertensive drugs, statin, anti-diabetic drugs were used as covariates. Logistic regression was conducted. RESULTS: The mean age of participants at baseline was 41.6 ± 7.9 years. We identified 1701 subjects who were active at both moments, 1246 who became active, 709 who became inactive, and 2210 who were inactive at both moments. Persistently inactive subjects presented a higher incidence of MS [10.4% (95%CI = 9.2-11.8%)]. In the adjusted logistic regression analyses, subjects that became active [OR = 0.55(95%CI = 0.40-0.74)] and persistently active [OR = 0.35(95%CI = 0.26-0.46)] were less likely to develop MS when compared with persistently inactive subjects. CONCLUSION: Persistently active subjects demonstrated the lowest likelihood of developing MS, while subjects who became active presented an attenuated risk.

Statin Eligibility in Primary Prevention: From a Risk-Based Strategy to a Personalized Approach Based on the Predicted Benefit.

Guidelines have recommended statin initiation based on the absolute cardiovascular risk. We tested the hypothesis that a strategy based on the predicted cardiovascular benefit, compared with the risk-based approach, modifies statin eligibility and the estimated benefit in a population in primary cardiovascular prevention. The study included 16,008 subjects (48 ± 6 years, 73% men) with low-density lipoprotein cholesterol levels of 70 to <190 mg/dl, not on lipid-lowering drugs, who underwent a routine health screening in a single center. For the risk-based strategy, criterion for statin eligibility was defined as a 10-year atherosclerotic cardiovascular disease (ASCVD) risk of ≥7.5%. In the benefit-based strategy, subjects were considered for statin according to the predicted absolute cardiovascular risk reduction, so that the number of statin candidates would be the same as in the risk-based strategy. The benefit-based strategy would replace 11% of statin candidates allocated in the risk-based approach with younger, lower risk subjects with higher low-density lipoprotein cholesterol. Using the benefit-based strategy, 13% of subjects with 5.0% to < 7.5% ASCVD risk would shift from a statin-ineligible to a statin-eligible status, whereas 24% of those with 7.5% to <10.0% ASCVD risk would become statin ineligible. These effects would transfer the benefit from higher to lower risk subjects. In the entire population, no clinically meaningful change in the benefit would be expected. In conclusion, switching from a risk-based strategy to a benefit-based approach, while keeping the same rate of statin use in the population, is expected to promote substantial changes in statin eligibility in subjects at intermediate cardiovascular risk, modifying the subpopulation to be benefited by the treatment.

Self-initiated physical activity is associated with high sensitivity C-reactive protein: A longitudinal study in 5,030 adults.

BACKGROUND AND AIMS: Structured regular exercise programs decrease high-sensitivity C-reactive protein (hsCRP), a marker of low-grade inflammation in adults. Longitudinal effects of self-initiated physical activity levels (PAL) on hsCRP are less clear. This study evaluated the association of longitudinal changes in hsCRP in relation to modifications in PAL, over time, in a large sample of adults. METHODS: Participants included 5030 adults, 4045 (80%) males, undergoing routine health screening examinations. Elevated level of hsCRP was defined as ≥3 mg/L. Self-reported PAL, height, weight, blood pressure and blood samples were collected at baseline and after a median of 2.9 years (P25th 1.97 and P75th 4.37 yrs). Participants were stratified according to their PAL at baseline and follow-up as: i) persistently physically inactive; ii) became physically inactive; iii) became physically active; iv) persistently physically active (active both at baseline and follow-up). RESULTS: Persistently physically active participants had lower odds of having higher hsCRP (OR = 0.35 [95% CI: 0.25 to 0.48]). The maintenance of high PAL was associated with lower hsCRP in both sexes (men: OR = 0.44 [0.30 to 0.65] and women: OR = 0.35 [0.16 to 0.76]). Participants with overweight/obesity (OR = 0.43 [95% CI: 0.29 to 0.63]) and smokers (OR = 0.123 [95% CI: 0.03 to 0.60]) who were persistently active had lower odds of having higher hsCRP compared to physically inactive peers. CONCLUSIONS: Self-initiated PAL was longitudinally associated with hsCRP in adults. The data suggest that the initiation or maintenance of PA attenuates the low-grade inflammatory state, independent of sex, body weight and smoking status.

Low-density lipoprotein-cholesterol lowering in individuals at intermediate cardiovascular risk: Percent reduction or target level?

BACKGROUND: Recommendations for blood cholesterol management differ across different guidelines. HYPOTHESIS: Lipid-lowering strategies based on low-density lipoprotein-cholesterol (LDL-c) percent reduction or target concentration may have different effects on the expected cardiovascular benefit in intermediate-risk individuals. METHODS: We selected individuals between 40 and 75 years of age with 10-year risk for atherosclerotic cardiovascular disease (ASCVD) between 5.0% and <7.5% who underwent a routine health screening. For every subject, we simulated a strategy based on a 40% LDL-c reduction (S40% ) and another strategy based on achieving LDL-c target ≤100 mg/dL (Starget-100 ). The cardiovascular benefit was estimated assuming a 22% relative risk reduction in major cardiovascular events for each 39 mg/dL of LDL-c lowered. RESULTS: The study comprised 1756 individuals (94% men, 52 ± 5 years old). LDL-c and predicted 10-year ASCVD risk would be slightly lower in S40% compared to Starget-100 . The number needed to treat to prevent 1 major cardiovascular event in 10 years (NNT10 ) would be 56 with S40% and 66 with Starget-100 . S40% would prevent more events in individuals with lower baseline LDL-c, whereas Starget-100 would be more protective in those with higher LDL-c. A dual-target strategy (40% minimum LDL-c reduction and achievement of LDL-c ≤100 mg/dL) would be associated with outcomes similar to those expected with the S40% (NNT10 = 55). CONCLUSIONS: In an intermediate-risk population, cardiovascular benefit from LDL-c lowering may be optimized by tailoring the treatment according to the baseline LDL-c or by setting a dual-target strategy (fixed dose statin plus achievement of target LDL-c concentration).

Association between clinical factors and self-underestimation of cardiovascular risk in subjects submitted to a routine health evaluation.

BACKGROUND: The perception of cardiovascular (CV) risk is essential for adoption of healthy behaviors. However, subjects underestimate their own risk. HYPOTHESIS: Clinical characteristics might be associated with self-underestimation of CV risk. METHODS: This is a retrospective, cross-sectional study of individuals submitted to routine health evaluation between 2006 and 2012, with calculated lifetime risk score (LRS) indicating intermediate or high risk for CV disease (CVD). Self-perception of risk was compared with LRS. Logistic regression analysis was performed to test the association between clinical characteristics and subjective underestimation of CV risk. RESULTS: Data from 5863 subjects (age 49.4 ± 7.1 years; 19.9% female) were collected for analysis. The LRS indicated an intermediate risk for CVD in 45.7% and a high risk in 54.3% of individuals. The self-perception of CV risk was underestimated compared with the LRS in 4918 (83.9%) subjects. In the adjusted logistic regression model, age (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.10-1.47 per 10 years, P = 0.001), smoking (OR: 1.99, 95% CI: 1.40-2.83, P < 0.001), dyslipidemia (OR: 1.21, 95% CI: 1.01-1.46, P = 0.045), physical activity (OR: 1.66, 95% CI: 1.36-2.02, P < 0.001), and use of antihypertensive (OR: 1.49, 95% CI: 1.15-1.92, P = 0.002) and lipid-lowering medications (OR: 2.13, 95% CI: 1.56-2.91, P < 0.001) were associated with higher chance of risk underestimation, whereas higher body mass index (OR: 0.92, 95% CI: 0.90-0.94, P < 0.001), depressive symptoms (OR: 0.46, 95% CI: 0.37-0.57, P < 0.001), and stress (OR: 0.41, 95% CI: 0.33-0.50, P < 0.001) decreased the chance. CONCLUSIONS: Among individuals submitted to routine medical evaluation, aging, smoking, dyslipidemia, physical activity, and use of antihypertensive and lipid-lowering medications were associated with higher chance of CV risk underestimation. Subjects with these characteristics may benefit from a more careful risk orientation.

Persistent Depressive Symptoms are Independent Predictors of Low-Grade Inflammation Onset Among Healthy Individuals / Sintomas Depressivos Persistentes são Preditores Independentes de Início de Inflamação de Baixo Grau em Indivíduos Saudáveis

Abstract Background: Depressive symptoms are independently associated with an increased risk of cardiovascular disease (CVD) among individuals with non-diagnosed CVD. The mechanisms underlying this association, however, remain unclear. Inflammation has been indicated as a possible mechanistic link between depression and CVD. Objectives: This study evaluated the association between persistent depressive symptoms and the onset of low-grade inflammation. Methods: From a database of 1,508 young (mean age: 41 years) individuals with no CVD diagnosis who underwent at least two routine health evaluations, 134 had persistent depressive symptoms (Beck Depression Inventory - BDI ≥ 10, BDI+) and 1,374 had negative symptoms at both time points (BDI-). All participants had been submitted to repeated clinical and laboratory evaluations at a regular follow-up with an average of 26 months from baseline. Low-grade inflammation was defined as plasma high-sensitivity C-Reactive Protein (CRP) concentrations > 3 mg/L. The outcome was the incidence of low-grade inflammation evaluated by the time of the second clinical evaluation. Results: The incidence of low-grade inflammation was more frequently observed in the BDI+ group compared to the BDI- group (20.9% vs. 11.4%; p = 0.001). After adjusting for sex, age, waist circumference, body mass index, levels of physical activity, smoking, and prevalence of metabolic syndrome, persistent depressive symptoms remained an independent predictor of low-grade inflammation onset (OR = 1.76; 95% CI: 1.03-3.02; p = 0.04). Conclusions: Persistent depressive symptoms were independently associated with low-grade inflammation onset among healthy individuals.

Resumo Fundamento: Sintomas depressivos estão associados de forma independente ao risco aumentado de doença cardiovascular (DCV) em indivíduos com DCV não diagnosticada. Os mecanismos subjacentes a essa associação, entretanto, não estão claros. Inflamação tem sido indicada como um possível elo mecanicista entre depressão e DCV. Objetivos: Este estudo avaliou a associação entre sintomas depressivos persistentes e o início de inflamação de baixo grau. Métodos: De um banco de dados de 1.508 indivíduos jovens (idade média: 41 anos) sem diagnóstico de DCV submetidos a pelo menos duas avaliações de saúde de rotina, 134 tinham sintomas depressivos persistentes (Inventário de Depressão de Beck - BDI ≥10, BDI+) e 1.374 não apresentavam sintomas em nenhuma das ocasiões (BDI-). Todos os participantes foram submetidos a repetidas avaliações clínicas e laboratoriais em seguimento regular, cuja média foi de 26 meses desde a condição basal. Definiu-se inflamação de baixo grau como concentração plasmática de proteína C reativa (PCR) ultrassensível > 3 mg/L. O desfecho foi a incidência de inflamação de baixo grau por ocasião da segunda avaliação clínica. Resultados: A incidência de inflamação de baixo grau foi maior no grupo BDI+ em comparação ao grupo BDI- (20,9% vs. 11,4%; p = 0,001). Após ajuste para sexo, idade, circunferência abdominal, índice de massa corporal, níveis de atividade física, tabagismo e prevalência de síndrome metabólica, os sintomas depressivos persistentes continuaram sendo um preditor independente de início de inflamação de baixo grau (OR = 1,76; IC 95%: 1,03-3,02; p = 0,04). Conclusões: Sintomas depressivos persistentes foram independentemente associados com início de inflamação de baixo grau em indivíduos saudáveis.

Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management.

BACKGROUND:: The best way to select individuals for lipid-lowering treatment in the population is controversial. OBJECTIVE:: In healthy individuals in primary prevention: to assess the relationship between cardiovascular risk categorized according to the V Brazilian Guideline on Dyslipidemia and the risk calculated by the pooled cohort equations (PCE); to compare the proportion of individuals eligible for statins, according to different criteria. METHODS:: In individuals aged 40-75 years consecutively submitted to routine health assessment at one single center, four criteria of eligibility for statin were defined: BR-1, BR-2 (LDL-c above or at least 30 mg/dL above the goal recommended by the Brazilian Guideline, respectively), USA-1 and USA-2 (10-year risk estimated by the PCE ≥ 5.0% or ≥ 7.5%, respectively). RESULTS:: The final sample consisted of 13,947 individuals (48 ± 6 years, 71% men). Most individuals at intermediate or high risk based on the V Brazilian Guideline had a low risk calculated by the PCE, and more than 70% of those who were considered at high risk had this categorization because of the presence of aggravating factors. Among women, 24%, 17%, 4% and 2% were eligible for statin use according to the BR-1, BR-2, USA-1 and USA-2 criteria, respectively (p < 0.01). The respective figures for men were 75%, 58%, 31% and 17% (p < 0.01). Eighty-five percent of women and 60% of men who were eligible for statin based on the BR-1 criterion would not be candidates for statin based on the USA-1 criterion. CONCLUSIONS:: As compared to the North American Guideline, the V Brazilian Guideline considers a substantially higher proportion of the population as eligible for statin use in primary prevention. This results from discrepancies between the risk stratified by the Brazilian Guideline and that calculated by the PCE, particularly because of the risk reclassification based on aggravating factors. FUNDAMENTO:: Existe controvérsia sobre a melhor forma de selecionar indivíduos para tratamento hipolipemiante na população. OBJETIVOS:: Em indivíduos saudáveis em prevenção primária: avaliar a relação entre o risco cardiovascular segundo a V Diretriz Brasileira de Dislipidemias e o risco calculado pelas pooled cohort equations (PCE); comparar a proporção de indivíduos elegíveis para estatinas, de acordo com diferentes critérios. MÉTODOS:: Em indivíduos de 40 a 75 anos submetidos consecutivamente a avaliação rotineira de saúde em um único centro, quatro critérios de elegibilidade para estatina foram definidos: BR-1, BR-2 (LDL-c acima ou pelo menos 30 mg/dL acima da meta preconizada pela diretriz brasileira, respectivamente), EUA-1 e EUA-2 (risco estimado pelas PCE em 10 anos ≥ 5,0% ou ≥ 7,5%, respectivamente). RESULTADOS:: Foram estudados 13.947 indivíduos (48 ± 6 anos, 71% homens). A maioria dos indivíduos de risco intermediário ou alto pela V Diretriz apresentou risco calculado pelas PCE baixo e mais de 70% daqueles considerados de alto risco o foram devido à presença de fator agravante. Foram elegíveis para estatina 24%, 17%, 4% e 2% das mulheres pelos critérios BR-1, BR-2, EUA-1 e EUA-2, respectivamente (p < 0,01). Os respectivos valores para os homens foram 75%, 58%, 31% e 17% (p < 0,01). Oitenta e cinco por cento das mulheres e 60% dos homens elegíveis para estatina pelo critério BR-1 não seriam candidatos pelo critério EUA-1. CONCLUSÕES:: Comparada à diretriz norte-americana, a V Diretriz Brasileira considera uma proporção substancialmente maior da população como elegível para estatina em prevenção primária. Isso se relaciona com discrepâncias entre o risco estratificado pela diretriz brasileira e o calculado pelas PCE, particularmente devido à reclassificação de risco baseada em fatores agravantes.

The Expected Cardiovascular Benefit of Plasma Cholesterol Lowering with or Without LDL-C Targets in Healthy Individuals at Higher Cardiovascular Risk.

BACKGROUND:: There is controversy whether management of blood cholesterol should be based or not on LDL-cholesterol (LDL-c) target concentrations. OBJECTIVES:: To compare the estimated impact of different lipid-lowering strategies, based or not on LDL-c targets, on the risk of major cardiovascular events in a population with higher cardiovascular risk. METHODS:: We included consecutive individuals undergoing a routine health screening in a single center who had a 10-year risk for atherosclerotic cardiovascular disease (ASCVD) ≥ 7.5% (pooled cohort equations, ACC/AHA, 2013). For each individual, we simulated two strategies based on LDL-c target (≤ 100 mg/dL [Starget-100] or ≤ 70 mg/dL [Starget-70]) and two strategies based on percent LDL-c reduction (30% [S30%] or 50% [S50%]). RESULTS:: In 1,897 subjects (57 ± 7 years, 96% men, 10-year ASCVD risk 13.7 ± 7.1%), LDL-c would be lowered from 141 ± 33 mg/dL to 99 ± 23 mg/dL in S30%, 71 ± 16 mg/dL in S50%, 98 ± 9 mg/dL in Starget-100, and 70 ± 2 mg/dL in Starget-70. Ten-year ASCVD risk would be reduced to 8.8 ± 4.8% in S50% and 8.9 ± 5.2 in Starget-70. The number of major cardiovascular events prevented in 10 years per 1,000 individuals would be 32 in S30%, 31 in Starget-100, 49 in S50%, and 48 in Starget-70. Compared with Starget-70, S50% would prevent more events in the lower LDL-c tertile and fewer events in the higher LDL-c tertile. CONCLUSIONS:: The more aggressive lipid-lowering approaches simulated in this study, based on LDL-c target or percent reduction, may potentially prevent approximately 50% more hard cardiovascular events in the population compared with the less intensive treatments. Baseline LDL-c determines which strategy (based or not on LDL-c target) is more appropriate at the individual level. FUNDAMENTOS:: Há controvérsias sobre se o controle do colesterol plasmático deve ou não se basear em metas de concentração de colesterol LDL (LDL-c). OBJETIVOS:: Comparar o impacto estimado de diferentes estratégias hipolipemiantes, baseadas ou não em metas de LDL-c, sobre o risco de eventos cardiovasculares maiores em uma população de risco cardiovascular mais elevado. MÉTODOS:: Foram incluídos indivíduos consecutivamente submetidos a uma avaliação rotineira de saúde em um único centro e que apresentavam um risco em 10 anos de doença cardiovascular aterosclerótica (DCVAS) ≥ 7,5% ("pooled cohort equations", ACC/AHA, 2013). Para cada indivíduo, foram simuladas duas estratégias baseadas em meta de LDL-c (≤ 100 mg/dL [Emeta-100] ou ≤ 70 mg/dL [Emeta-70]) e duas estratégias baseadas em redução percentual do LDL-c (30% [E30%] ou 50% [E50%]). RESULTADOS:: Em 1.897 indivíduos (57 ± 7 anos, 96% homens, risco em 10 anos de DCVAS 13,7 ± 7,1%), o LDL-c seria reduzido de 141 ± 33 mg/dL para 99 ± 23 mg/dL na E30%, 71 ± 16 mg/dL na E50%, 98 ± 9 mg/dL na Emeta-100 e 70 ± 2 mg/dL na Emeta-70. O risco em 10 anos de DCVAS seria reduzido para 8,8 ± 4,8% na E50% e para 8,9 ± 5,2 na Emeta-70. O número de eventos cardiovasculares maiores prevenidos em 10 anos por 1.000 indivíduos seria de 32 na E30%, 31 na Emeta-100, 49 na E50% e 48 na Emeta-70. Em comparação com a Emeta-70, a E50% evitaria mais eventos no tercil inferior de LDL-c e menos eventos no tercil superior de LDL-c. CONCLUSÕES:: As abordagens hipolipemiantes mais agressivas simuladas neste estudo, com base em meta de LDL-c ou redução percentual, podem potencialmente prevenir cerca de 50% mais eventos cardiovasculares graves na população em comparação com os tratamentos menos intensivos. Os níveis basais de LDL-c determinam qual estratégia (baseada ou não em meta de LDL-c) é mais apropriada para cada indivíduo.

Persistent Depressive Symptoms are Independent Predictors of Low-Grade Inflammation Onset Among Healthy Individuals.

Background: Depressive symptoms are independently associated with an increased risk of cardiovascular disease (CVD) among individuals with non-diagnosed CVD. The mechanisms underlying this association, however, remain unclear. Inflammation has been indicated as a possible mechanistic link between depression and CVD. Objectives: This study evaluated the association between persistent depressive symptoms and the onset of low-grade inflammation. Methods: From a database of 1,508 young (mean age: 41 years) individuals with no CVD diagnosis who underwent at least two routine health evaluations, 134 had persistent depressive symptoms (Beck Depression Inventory - BDI ≥ 10, BDI+) and 1,374 had negative symptoms at both time points (BDI-). All participants had been submitted to repeated clinical and laboratory evaluations at a regular follow-up with an average of 26 months from baseline. Low-grade inflammation was defined as plasma high-sensitivity C-Reactive Protein (CRP) concentrations > 3 mg/L. The outcome was the incidence of low-grade inflammation evaluated by the time of the second clinical evaluation. Results: The incidence of low-grade inflammation was more frequently observed in the BDI+ group compared to the BDI- group (20.9% vs. 11.4%; p = 0.001). After adjusting for sex, age, waist circumference, body mass index, levels of physical activity, smoking, and prevalence of metabolic syndrome, persistent depressive symptoms remained an independent predictor of low-grade inflammation onset (OR = 1.76; 95% CI: 1.03-3.02; p = 0.04). Conclusions: Persistent depressive symptoms were independently associated with low-grade inflammation onset among healthy individuals.

Fundamento: Sintomas depressivos estão associados de forma independente ao risco aumentado de doença cardiovascular (DCV) em indivíduos com DCV não diagnosticada. Os mecanismos subjacentes a essa associação, entretanto, não estão claros. Inflamação tem sido indicada como um possível elo mecanicista entre depressão e DCV. Objetivos: Este estudo avaliou a associação entre sintomas depressivos persistentes e o início de inflamação de baixo grau. Métodos: De um banco de dados de 1.508 indivíduos jovens (idade média: 41 anos) sem diagnóstico de DCV submetidos a pelo menos duas avaliações de saúde de rotina, 134 tinham sintomas depressivos persistentes (Inventário de Depressão de Beck - BDI ≥10, BDI+) e 1.374 não apresentavam sintomas em nenhuma das ocasiões (BDI-). Todos os participantes foram submetidos a repetidas avaliações clínicas e laboratoriais em seguimento regular, cuja média foi de 26 meses desde a condição basal. Definiu-se inflamação de baixo grau como concentração plasmática de proteína C reativa (PCR) ultrassensível > 3 mg/L. O desfecho foi a incidência de inflamação de baixo grau por ocasião da segunda avaliação clínica. Resultados: A incidência de inflamação de baixo grau foi maior no grupo BDI+ em comparação ao grupo BDI- (20,9% vs. 11,4%; p = 0,001). Após ajuste para sexo, idade, circunferência abdominal, índice de massa corporal, níveis de atividade física, tabagismo e prevalência de síndrome metabólica, os sintomas depressivos persistentes continuaram sendo um preditor independente de início de inflamação de baixo grau (OR = 1,76; IC 95%: 1,03-3,02; p = 0,04). Conclusões: Sintomas depressivos persistentes foram independentemente associados com início de inflamação de baixo grau em indivíduos saudáveis.

Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management / Estratificação de Risco Cardiovascular e Elegibilidade para Estatina com Base na Diretriz Brasileira vs. Norte-Americana para Manejo do Colesterol

Abstract Background: The best way to select individuals for lipid-lowering treatment in the population is controversial. Objective: In healthy individuals in primary prevention: to assess the relationship between cardiovascular risk categorized according to the V Brazilian Guideline on Dyslipidemia and the risk calculated by the pooled cohort equations (PCE); to compare the proportion of individuals eligible for statins, according to different criteria. Methods: In individuals aged 40-75 years consecutively submitted to routine health assessment at one single center, four criteria of eligibility for statin were defined: BR-1, BR-2 (LDL-c above or at least 30 mg/dL above the goal recommended by the Brazilian Guideline, respectively), USA-1 and USA-2 (10-year risk estimated by the PCE ≥ 5.0% or ≥ 7.5%, respectively). Results: The final sample consisted of 13,947 individuals (48 ± 6 years, 71% men). Most individuals at intermediate or high risk based on the V Brazilian Guideline had a low risk calculated by the PCE, and more than 70% of those who were considered at high risk had this categorization because of the presence of aggravating factors. Among women, 24%, 17%, 4% and 2% were eligible for statin use according to the BR-1, BR-2, USA-1 and USA-2 criteria, respectively (p < 0.01). The respective figures for men were 75%, 58%, 31% and 17% (p < 0.01). Eighty-five percent of women and 60% of men who were eligible for statin based on the BR-1 criterion would not be candidates for statin based on the USA-1 criterion. Conclusions: As compared to the North American Guideline, the V Brazilian Guideline considers a substantially higher proportion of the population as eligible for statin use in primary prevention. This results from discrepancies between the risk stratified by the Brazilian Guideline and that calculated by the PCE, particularly because of the risk reclassification based on aggravating factors.

Resumo Fundamento: Existe controvérsia sobre a melhor forma de selecionar indivíduos para tratamento hipolipemiante na população. Objetivos: Em indivíduos saudáveis em prevenção primária: avaliar a relação entre o risco cardiovascular segundo a V Diretriz Brasileira de Dislipidemias e o risco calculado pelas pooled cohort equations (PCE); comparar a proporção de indivíduos elegíveis para estatinas, de acordo com diferentes critérios. Métodos: Em indivíduos de 40 a 75 anos submetidos consecutivamente a avaliação rotineira de saúde em um único centro, quatro critérios de elegibilidade para estatina foram definidos: BR-1, BR-2 (LDL-c acima ou pelo menos 30 mg/dL acima da meta preconizada pela diretriz brasileira, respectivamente), EUA-1 e EUA-2 (risco estimado pelas PCE em 10 anos ≥ 5,0% ou ≥ 7,5%, respectivamente). Resultados: Foram estudados 13.947 indivíduos (48 ± 6 anos, 71% homens). A maioria dos indivíduos de risco intermediário ou alto pela V Diretriz apresentou risco calculado pelas PCE baixo e mais de 70% daqueles considerados de alto risco o foram devido à presença de fator agravante. Foram elegíveis para estatina 24%, 17%, 4% e 2% das mulheres pelos critérios BR-1, BR-2, EUA-1 e EUA-2, respectivamente (p < 0,01). Os respectivos valores para os homens foram 75%, 58%, 31% e 17% (p < 0,01). Oitenta e cinco por cento das mulheres e 60% dos homens elegíveis para estatina pelo critério BR-1 não seriam candidatos pelo critério EUA-1. Conclusões: Comparada à diretriz norte-americana, a V Diretriz Brasileira considera uma proporção substancialmente maior da população como elegível para estatina em prevenção primária. Isso se relaciona com discrepâncias entre o risco estratificado pela diretriz brasileira e o calculado pelas PCE, particularmente devido à reclassificação de risco baseada em fatores agravantes.

The Expected Cardiovascular Benefit of Plasma Cholesterol Lowering with or Without LDL-C Targets in Healthy Individuals at Higher Cardiovascular Risk / Benefício Cardiovascular Esperado pela Redução do Colesterol Plasmático com ou sem Metas de LDL-C em Indivíduos Saudáveis de Risco Cardiovascular mais Elevado

Abstract Background: There is controversy whether management of blood cholesterol should be based or not on LDL-cholesterol (LDL-c) target concentrations. Objectives: To compare the estimated impact of different lipid-lowering strategies, based or not on LDL-c targets, on the risk of major cardiovascular events in a population with higher cardiovascular risk. Methods: We included consecutive individuals undergoing a routine health screening in a single center who had a 10-year risk for atherosclerotic cardiovascular disease (ASCVD) ≥ 7.5% (pooled cohort equations, ACC/AHA, 2013). For each individual, we simulated two strategies based on LDL-c target (≤ 100 mg/dL [Starget-100] or ≤ 70 mg/dL [Starget-70]) and two strategies based on percent LDL-c reduction (30% [S30%] or 50% [S50%]). Results: In 1,897 subjects (57 ± 7 years, 96% men, 10-year ASCVD risk 13.7 ± 7.1%), LDL-c would be lowered from 141 ± 33 mg/dL to 99 ± 23 mg/dL in S30%, 71 ± 16 mg/dL in S50%, 98 ± 9 mg/dL in Starget-100, and 70 ± 2 mg/dL in Starget-70. Ten-year ASCVD risk would be reduced to 8.8 ± 4.8% in S50% and 8.9 ± 5.2 in Starget-70. The number of major cardiovascular events prevented in 10 years per 1,000 individuals would be 32 in S30%, 31 in Starget-100, 49 in S50%, and 48 in Starget-70. Compared with Starget-70, S50% would prevent more events in the lower LDL-c tertile and fewer events in the higher LDL-c tertile. Conclusions: The more aggressive lipid-lowering approaches simulated in this study, based on LDL-c target or percent reduction, may potentially prevent approximately 50% more hard cardiovascular events in the population compared with the less intensive treatments. Baseline LDL-c determines which strategy (based or not on LDL-c target) is more appropriate at the individual level.

Resumo Fundamentos: Há controvérsias sobre se o controle do colesterol plasmático deve ou não se basear em metas de concentração de colesterol LDL (LDL-c). Objetivos: Comparar o impacto estimado de diferentes estratégias hipolipemiantes, baseadas ou não em metas de LDL-c, sobre o risco de eventos cardiovasculares maiores em uma população de risco cardiovascular mais elevado. Métodos: Foram incluídos indivíduos consecutivamente submetidos a uma avaliação rotineira de saúde em um único centro e que apresentavam um risco em 10 anos de doença cardiovascular aterosclerótica (DCVAS) ≥ 7,5% ("pooled cohort equations", ACC/AHA, 2013). Para cada indivíduo, foram simuladas duas estratégias baseadas em meta de LDL-c (≤ 100 mg/dL [Emeta-100] ou ≤ 70 mg/dL [Emeta-70]) e duas estratégias baseadas em redução percentual do LDL-c (30% [E30%] ou 50% [E50%]). Resultados: Em 1.897 indivíduos (57 ± 7 anos, 96% homens, risco em 10 anos de DCVAS 13,7 ± 7,1%), o LDL-c seria reduzido de 141 ± 33 mg/dL para 99 ± 23 mg/dL na E30%, 71 ± 16 mg/dL na E50%, 98 ± 9 mg/dL na Emeta-100 e 70 ± 2 mg/dL na Emeta-70. O risco em 10 anos de DCVAS seria reduzido para 8,8 ± 4,8% na E50% e para 8,9 ± 5,2 na Emeta-70. O número de eventos cardiovasculares maiores prevenidos em 10 anos por 1.000 indivíduos seria de 32 na E30%, 31 na Emeta-100, 49 na E50% e 48 na Emeta-70. Em comparação com a Emeta-70, a E50% evitaria mais eventos no tercil inferior de LDL-c e menos eventos no tercil superior de LDL-c. Conclusões: As abordagens hipolipemiantes mais agressivas simuladas neste estudo, com base em meta de LDL-c ou redução percentual, podem potencialmente prevenir cerca de 50% mais eventos cardiovasculares graves na população em comparação com os tratamentos menos intensivos. Os níveis basais de LDL-c determinam qual estratégia (baseada ou não em meta de LDL-c) é mais apropriada para cada indivíduo.

Extremely elevated HDL-cholesterol levels are not associated with increased carotid intima-media thickness: data from ELSA Brasil.

BACKGROUND: There is evidence that extremely elevated high-density lipoprotein cholesterol (HDL-c), that is, hyperalphalipoproteinemia (HALP) may indicate dysfunctional HDL, conferring increased cardiovascular risk. OBJECTIVE: We studied carotid intima-media thickness (cIMT) a marker of subclinical vascular disease according to HDL-c distribution. METHODS: cIMT was studied in subjects with "normal" HDL-c levels (HDL-c 40-50 mg/dL for men; 50-60 mg/dL for women, mean 49.6 ± 5.7 mg/dL, n = 3226); in those with HALP (HDL-c ≥90 mg/dL for both sexes, mean 101.2 ± 10 mg/dL, n = 264) and according to HDL-c quintile distribution (n = 9779). Multiple linear regression was used to test the association of HDL-c and cIMT. RESULTS: Subjects with HALP were older (54.5 ± 9.6 vs 51.1 ± 8.8 years, P < .001); more frequently females (86.4% vs 49%, P < .001); and presented a lower burden of risk factors: hypertension (24.6% vs 32.7%, P = .009), diabetes (10.2% vs 20.4%, P < .001), and obesity (18.6% vs 37.6%, P < .001). A similar profile was seen with higher HDL-c quintiles in the whole study population. When compared to normal HDL-c values, HALP was associated with lower maximal cIMT (0.779 ± 0.189 mm vs 0.818 ± 0.200 mm, P = .002), and there was a lower prevalence of individuals with cIMT ≥ 75(th) percentile for age and gender or high cIMT (17.5% vs 26.2%, P = .003). After multivariate analysis, no association was seen between HALP and increasing cIMT values, indeed the 5(th) HDL-c quintile was associated with lower risk of high cIMT (OR = 0.80; 95% CI = 0.68-0.95). CONCLUSION: HALP is associated with lower cIMT and does not indicate a pro-atherogenic phenotype.

Elevated gamma-glutamyl transferase is associated with subclinical inflammation independent of cardiometabolic risk factors in an asymptomatic population: a cross-sectional study.

BACKGROUND: Serum Gamma-Glutamyl Transferase (GGT), a marker of oxidative stress, has been suggested to be independently associated with cardiovascular disease (CVD) events. We examined the association of serum GGT levels with the burden of subclinical inflammation across a spectrum of metabolic conditions. METHODS: We evaluated 5,446 asymptomatic subjects (43 ± 10 years, 78 % males) who had an employer-sponsored physical between 2008 and 2010. Highly sensitivity C-reactive protein (hsCRP) was measured as a marker of underlying systemic inflammation. A linear regression of GGT quartiles with log transformed hsCRP and a multivariate logistic regression of GGT quartiles with elevated hsCRP (≥3 mg/L) were performed. RESULTS: Median GGT was 31 IU/l (IQR: 22-45 IU/l), 1025 (19 %) had hsCRP ≥ 3 mg/L. The median hsCRP increased with GGT quartiles (Q1: 0.9 mg/L, Q2: 1.1 mg/L, Q3: 1.4 mg/L, Q4: 1.6 mg/L, p < 0.001). Linear regression models showed GGT in the fourth quartile was associated with 0.45 mg/L (95 % CI 0.35, 0.54, p < 0.001) increase in log transformed hsCRP adjusting for risk factors. The Odds Ratio (OR) for an elevated hsCRP (≥3 mg/L) also increased with higher GGT quartiles; GGT Q2 1.44 (95 % CI 1.12, 1.85), GGT Q3 1.89 (95 % CI 1.45, 2.46), GGT Q4 2.22 (95 % CI 1.67, 2.95), compared to GGT Q1. The strength of association increased in the presence of and combination of metabolic conditions. CONCLUSION: In our cohort of asymptomatic individuals a higher serum GGT level was independently associated with increased burden of subclinical inflammation across metabolic states. These findings may explain GGT association with increased CVD risk.

Obesity Modifies the Effect of Fitness on Heart Rate Indices during Exercise Stress Testing in Asymptomatic Individuals.

OBJECTIVE: To assess the impact of aerobic fitness on exercise heart rate (HR) indices in an asymptomatic cohort across different body mass index (BMI) categories. METHODS: We performed a cross-sectional analysis of 506 working-class Brazilian subjects, free of known clinical cardiovascular disease(e.g. ischemic heart disease and stroke) who underwent an exercise stress test. RESULTS: There was a significant trend towards decreased HR at peak exercise, HR recovery and chronotropic index (CI) measures as BMI increased, but resting HR increased significantly across BMI categories. In multivariate analysis, the change in CI per unit change in metabolic equivalents of task was greater among the obese subjects than the normal-weight (2.7 vs. ­0.07; p interaction = 0.029)and overweight (2.7 vs. 0.7; p interaction = 0.044) subjects. A similar pattern was seen with peak HR and HR recovery, although the formal tests of interaction did not achieve statistical significance. CONCLUSION: Our findings strongly suggest that fitness is associated with a favorable HR profile and is modified by BMI. Intervention programs should place emphasis on fitness and not only on weight loss.

Obesity and metabolic phenotypes (metabolically healthy and unhealthy variants) are significantly associated with prevalence of elevated C-reactive protein and hepatic steatosis in a large healthy Brazilian population.

BACKGROUND: Among the obese, the so-called metabolically healthy obese (MHO) phenotype is thought to confer a lower CVD risk as compared to obesity with typical associated metabolic changes. The present study aims to determine the relationship of different subtypes of obesity with inflammatory-cardiometabolic abnormalities. METHODS: We evaluated 5,519 healthy, Brazilian subjects (43 ± 10 years, 78% males), free of known cardiovascular disease. Those with <2 metabolic risk factors (MRF) were considered metabolically healthy, and those with BMI ≥ 25 kg/m(2) and/or waist circumference meeting NCEP criteria for metabolic syndrome as overweight/obese (OW). High sensitivity C reactive protein (hsCRP) was measured to assess underlying inflammation and hepatic steatosis (HS) was determined via abdominal ultrasound. RESULTS: Overall, 40% of OW individuals were metabolically healthy, and 12% normal-weight had ≥2 MRF. The prevalence of elevated CRP (≥3 mg/dL) and HS in MHO versus normal weight metabolically healthy group was 22% versus 12%, and 40% versus 8% respectively (P < 0.001). Both MHO individuals and metabolically unhealthy normal weight (MUNW) phenotypes were associated with elevated hsCRP and HS. CONCLUSION: Our study suggests that MHO and MUNW phenotypes may not be benign and physicians should strive to treat individuals in these subgroups to reverse these conditions.

Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk.

OBJECTIVES: To determine the relationship between clinically relevant blood pressure (BP) groups and nonalcoholic fatty liver disease (NAFLD) presence and severity especially in the milieu of other metabolic risk factors. PATIENTS AND METHODS: From a Brazilian cohort of 5362 healthy middle-aged men and women who presented for yearly physical examination and testing, the cross-sectional relationship between BP categories and NAFLD was assessed. BP groups were categorized as normal, prehypertension (PHT), and hypertension (HTN) according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classification. NAFLD was ultrasound diagnosed, excluding persons with alcohol consumption more than 20 g/day. NAFLD severity was estimated using the Fibrosis-4 (FIB-4) risk score. RESULTS: The prevalence of NAFLD was 36.2%. Participants with NAFLD were older (mean 46 vs. 42 years, P < 0.001) and had elevated BMI (mean 29.0 vs. 24.7 kg/m, P < 0.001). The prevalence of NAFLD among persons with normal BP, PHT, and HTN was 16.5, 37.5, and 59.3%, respectively. In multivariate analyses, PHT and HTN were associated with elevated odds of NAFLD (PHT-adjusted odds ratio 1.3, 95% confidence interval 1.1, 1.6; HTN-adjusted odds ratio 1.8, 95% confidence interval 1.4-2.3) compared with normal BP. Among nonobese hypertensive patients, BP control (BP < 140/90 mmHg) was independently associated with 40% lower odds of prevalent NAFLD. Compared with hypertensive patients, both normotensive individuals and prehypertensive patients were more likely to have a low fibrosis risk (FIB-4 ≥ 1.3). CONCLUSION: Prevalent NAFLD may be seen early in the development of hypertension, even in the absence of other metabolic risk factors. Controlling BP among nonobese hypertensive patients may be beneficial in preventing or limiting NAFLD.

Calculated and perceived cardiovascular risk in asymptomatic subjects submitted to a routine medical evaluation: The perception gap.

BACKGROUND: Poor adherence to medical treatment represents a major health problem. A subject's misperception of his own cardiovascular risk has been indicated as a key driver for low compliance with preventive measures. This study analysed the relationship between objectively calculated short- and long-term cardiovascular risk and its subjective perception. DESIGN: Cross-sectional study in asymptomatic Brazilian subjects. METHODS: Individuals (N = 6544, mean age 49.1 ± 7 years, 22.2% female) who underwent a routine mandatory health evaluation were studied. A questionnaire in which each individual rated his own cardiovascular risk as low, intermediate or high according to his own perception was used. The 10-year and lifetime cardiovascular risk were calculated respectively using the Framingham risk (FRS) and Lifetime risk (LRS) scores. Individuals were classified as hypo-perceivers (i.e. perceived risk lower than estimated risk), normo-perceivers (i.e. perceived risk coincident with estimated risk) and hyper-perceivers (i.e. perceived risk higher than estimated risk). RESULTS: Cardiovascular risk, using the FRS, was low in 77.9% (N = 5071), intermediate in 14.4% (N = 939) and high in 7.7% (N = 499) of subjects. Cardiovascular risk, using the LRS, was low in 7.6% (N = 492), intermediate in 43.1% (N = 2787) and high in 49.3% (N = 3184) of the study population. The prevalence of normo-perceivers was 57.6% using the FRS and only 20.6% using the LRS. Using the LRS, 72.3% of the intermediate and 91.2% of the high-risk subjects were hypo-perceivers. CONCLUSIONS: In a large sample of asymptomatic individuals, there was a gap between calculated and perceived cardiovascular risk. Using a long-term risk score, most of the intermediate- and high-risk subjects were hypo-perceivers.

Relation of physical activity to prevalence of nonalcoholic Fatty liver disease independent of cardiometabolic risk.

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance and has been linked with increased cardiovascular risk. Although physical activity (PA) and lifestyle modification are often recommended in patients at cardiovascular risk, the benefit across the cardiometabolic risk spectrum is unclear. We aimed to evaluate the relation of PA and NAFLD independent of metabolic syndrome (MS) or obesity. We evaluated 5,743 healthy Brazilian subjects (43 ± 10 years, 79% men) without clinical coronary heart disease from December 2008 to December 2010. NAFLD was diagnosed using ultrasounds, and self-reported PA was assessed using the International Physical Activity Questionnaire scale. In a multivariate logistic regression adjusted for cardiometabolic risk factors, we evaluated for an independent association of NAFLD and PA. In the total study population, NAFLD prevalence was 36% (n = 2,075), obesity 23% (1,300), and MS 20% (1,152). NAFLD was more prevalent in subjects with MS (74%) than those without (26%) and in those obese (73%) than in those nonobese (25%). Overall, 1,305 (23%) subjects reported low activity, 1,990 (35%) moderate activity, and 2,448 (42%) high activity. NAFLD prevalence was lower at higher levels of reported PA (low 45%, moderate 38%, and high 30%, p <0.001). After adjusting for risk factors, subjects with high activity had lower odds of having NAFLD. The favorable association was independent of obesity or MS. In conclusion, PA presents a dose-response association with NAFLD independent of the MS or obesity. Our results are compatible with the idea that benefits of PA are relevant to everyone regardless of cardiometabolic risk.