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Atherosclerosis is an inflammatory disease. Coronary artery calcium (CAC) is a marker of atherosclerotic disease events and mortality risk. Increased GlycA, an emerging marker of inflammation, is associated with a higher risk for coronary artery disease (CAD). However, there is conflicting evidence on whether GlycA predicts subclinical CAD progression. We hypothesized that GlycA can predict subclinical CAC incidence/progression in healthy participants. We included 2,690 ELSA-Brasil cohort participants without cardiovascular/chronic inflammatory disease not receiving statin therapy who had GlycA levels measured and 2 interval CAC assessments between 2010 and 2018. Multivariable logistic and linear regression models were computed to evaluate GlycA as a predictor of CAC incidence and progression. CAC incidence required a baseline CAC of 0. CAC progression required a baseline CAC >0. The mean age of participants was 48.6 ± 7.7 years, 56.7% were women, and 54.6% and 16.1% (429 of 2,690) were White and Black, respectively. The mean CAC interscan period was 5.1 ± 0.9 years, the mean GlycA level was 414.7 ± 65 µmol/L, and the incidence of CAC was 13.1% (280 of 2,129). The GlycA level odds ratio for CAC incidence was 1.002 (95% confidence interval 1.0005 to 1.005, p = 0.016), adjusted for demographics, lifestyle, a family history of early CAD (≤60 years), lipids, and co-morbidities. The GlycA (≤p25 vs ≥p75) odds ratio for CAC progression (Berry definition) was 1.77 (95% confidence interval 1.07 to 2.96, p = 0.03) in a similar multivariable-adjusted model. Higher GlycA levels were associated with CAC incidence and progression in a healthy Brazilian cohort.

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BACKGROUND: Statins are the main strategy to reduce dyslipidemia-related cardiovascular risk. Nevertheless, there is scarce evidence on the real-world statins use in primary care settings in low-middle-income countries. OBJECTIVE: We conducted a cross-sectional retrospective study using anonymized data routinely collected by community health workers in Brazil aimed to evaluate statin use and associated factors in a primary prevention population with cardiovascular risk enhancers. METHODS: Study population consisted of adults with hypertension, diabetes, and/or dyslipidemia. The primary and secondary outcomes were the proportion of individuals self-reporting statins use on any dose and high-dose statins/high-intensity lipid-lowering therapy (LLT), respectively. RESULTS: Of the 2,133,900 adult individuals in the database, 415,766 (19.5%) were included in the study cohort. From this cohort, 89.1% had hypertension, 28.9% diabetes, and 5.5% dyslipidemia. The mean age was 61.5 (standard deviation 14.5) years, 63.4% were female, and 61.0% were of mixed-race. Only 2.6% and 0.1% of individuals self-reported the use of statins and high-dose statins/high-intensity LLT, respectively. Older age (odds ratio [OR] 1.96; 95% confidence interval [CI] 1.88, 2.05, p < 0.001), living in the South region of Brazil (OR 4.39; 95% CI 3.97, 4.85, p < 0.001), heart failure (OR 2.60; 95% CI 2.33, 2.89, p < 0.001), chronic kidney disease (OR 1.49; 95% CI 1.35, 1.64, p < 0.001), and anti-hypertensive medications use (OR 4.38; 95% CI 4.07, 4.71, p < 0.001) were independently associated with statin use. CONCLUSION: In a real-world evidence study analyzing data routinely collected in a digitized primary care setting, we observed a very low use of statins in a primary prevention population with cardiovascular risk enhancers in Brazil. Socio-demographic factors and co-morbidities were associated with higher statins use rates.

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Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.

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AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.

Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).

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Abstract Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder, characterized by alterations in the catabolism of chylomicrons and by increased levels of plasma triglycerides. It has been shown that about 60-90% of FCS patients have biallelic mutations in the LPL gene and the remaining patients have mutations in genes encoding proteins closely related to LPL function. The objective of this manuscript is to illustrate the different clinical scenarios of FCS presentation, and to guide practitioners on the usefulness of genetic tests in each of them. To this end, several published papers about recommendations for the diagnosis of FCS are discussed briefly, in addition to the presentation of several hypothetical cases, highlighting different clinical presentations and possible associated genetic findings. These cases illustrate the multiplicity of potential aspects of family history, clinical manifestations, biochemical parameters, and patterns of genetic variants found in genomic analyses of FCS.

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BACKGROUND AND OBJECTIVE: To compare high-sensitivity C-reactive protein (hsCRP) levels according to smoking status and physical activity (PA) changes in adults. METHODS: The sample consisted of 6028 participants (4833 men) who underwent a voluntary routine health evaluation at the Preventive Medicine Center at the Hospital Israelita Albert Einstein, Sao Paulo, Brazil, from January 2007 to December 2013. Data were collected at baseline and follow-up (2.7±1.6 years). Plasma hsCRP (in mg/L) was analyzed in both moments. Smoking status was obtained through a self-reported questionnaire, being participants classified as non-smokers, once smokers (report smoking at baseline or follow-up), and persistently smokers (reported smoking at both baseline and follow-up). PA was assessed by questionnaire in both moments, being participants classified as persistently inactive, became inactive, became active, and persistently active. The Rank Analysis of Covariance was used to compare hsCRP follow-up values according to smoking and physical activity status. RESULTS: Persistently smokers showed significantly higher median values of hsCRP at follow-up (1.3 mg/L, IQR:0.6-2.8) than once smokers (1.1 mg/L, IQR: 0.6-2.4) and non-smokers (1.0 mg/L, IQR: 0.5-2.2), even considering covariates (p<0.001). Persistently actives had lower levels of hsCRP at follow-up when compared to persistently inactive in the three smoking status groups (non-smokers p<0.001, once smokers p = 0.001, and persistently smokers p = 0.037). CONCLUSION: Persistently active participants had lower hsCRP values at follow-up than those persistently inactive in all the smoking status groups. Regular practice of PA is an important strategy for facing low-grade inflammation, even among smokers.

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OBJECTIVE: Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk. METHODS: A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group. RESULTS: Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25th risk percentile, those at the ≥75th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6. CONCLUSIONS: We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals.

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Obesity is a prevalent chronic disorder and a well-known risk factor for cardiovascular disease. However, the evidence of treating obesity for primary prevention of major cardiovascular events is still scarce and controversial. In this review, we provided a comprehensive description of the current evidence in treating obesity regarding cardiovascular protection. Bariatric surgery appears to be the most robust method to reduce events in people without established cardiovascular disease. High compliance to lifestyle interventions can further reduce cardiovascular risk. Concerning pharmacological therapies, a post hoc analysis from SUSTAIN-6 and a meta-analysis from STEP trials suggest that semaglutide, a GLP-1 receptor agonist, could reduce cardiovascular events in people without established cardiovascular disease. The first study addressed specifically a high-risk population with diabetes and, the second, low- or intermediary-risk individuals without diabetes. Tirzepatide, a novel dual GIP/GLP-1 agonist, although not yet tested in specific cardiovascular outcomes trials, could be an alternative since it induces loss in weight similar to the achieved by bariatric surgery. Therefore, extrapolated data in distinct baseline cardiovascular risk populations suggest that these two drugs could be used in primary prevention with the aim of preventing cardiovascular events, but the grade of this evidence is still low. Specifically designed studies are needed to address this specific topic.

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Background: GlycA is a novel glycoprotein biomarker of systemic inflammation and cardiovascular risk. Our objective was to assess the levels of GlycA in individuals with hypothyroidism. We also explored whether levothyroxine (LT4)-treated patients had different levels of GlycA, with attention to thyrotropin (TSH) levels. Methods: We performed a cross-sectional analysis, using baseline data from the ELSA-Brasil cohort study. We included only participants with serum TSH and GlycA levels measurements, using magnetic resonance spectroscopy (n = 4745). We excluded individuals with endogenous hyperthyroidism and those using drugs impacting thyroid function. Participants not taking LT4 and whose serum TSH was 0.4-4.0 mIU/L were classified as euthyroid (EU) and those with elevated TSH as undiagnosed hypothyroidism (UH). For those on LT4 (n = 345), adequacy of treatment was defined as TSH within the reference range. Those with TSH <0.4 mIU/L were considered over-treated (OT), and those >4.0 mIU/L, under-treated (UT). Both (UT+OT) were considered inadequately treated (IT). Group comparisons were performed by Kruskal-Wallis, adjusted Chi-square, and the post hoc Dunn test. Additional subgroup analysis were performed in patients with circulating thyroperoxidase antibodies (TPO-Ab+). Respective multivariable analyses were performed to evaluate the relationship between thyroid-related variables and GlycA levels (Generalized Linear Model), as well as an abnormal GlycA (>400 µmol/L; Logistic Binary Regression). Results: The prevalence rate of UH was 9.8% (467/4745) and, among those on LT4, only 61.7% (213/345) were adequately treated (AT). GlycA levels were higher in IT in comparison to EU (429 vs. 410 µmol/L, p < 0.01) but did not differ between UH (413 µmol/L) and euthyroidism. However, the subgroup analysis of those TPO-Ab+ showed that not only those with IT, but also those with UH, had higher levels of GlycA in comparison to euthyroidism (423 and 424 vs. 402 µmol/L, p = 0.04). This association between higher levels of GlycA and IT was maintained even in multivariable analysis (odds ratio 1.53, confidence interval 1.03 to 2.31) Lower levels of GlycA were detected in AT (405 µmol/L,) compared with OT (432 µmol/L, 0.04) and UT (423 µmol/L, p = 0.02). Conclusions: Patients with IT, both OT and UT, had higher GlycA levels, which may be associated with low-grade systemic inflammation and, possibly, increased cardiovascular risk.

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Elevated levels of glycoprotein acetylation (GlycA) and C-reactive protein (CRP) have been associated with carotid artery plaque (CAP). However, it is not yet established if elevations in both inflammatory biomarkers provide incremental association with CAP. This study aimed evaluate the cross-sectional association of high CRP and GlycA with CAP at baseline participants from the ELSA-Brasil adult cohort. Participants with information on CRP, GlycA, and CAP with neither previous cardiovascular disease nor CRP >10 mg/L were included. High GlycA and CRP were defined as values within upper quintile and >3 mg/L, respectively. Participants were classified into 4 groups: 1. nonelevated CRP/GlycA (reference group); 2. elevated CRP alone; 3. elevated GlycA alone; and 4. both elevated. The analysis included 4,126 participants with median age of 50 years-old, being 54.2% of women. Prevalence of CAP was 36.1%. Participants with high CRP had the highest frequency of obesity, whereas participants with high GlycA presented higher cardiovascular risk factor burden and were more likely to have CAP than the reference group (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.11 to 1.73), persisting after multivariable adjustment (OR 1.37, 95% CI 1.02 to 1.83). Participants with both elevated CRP and GlycA were more likely to have CAP in crude (OR 1.35, 95% CI 1.10 to 1.65) but not in adjusted models. The findings suggest potential different biologic pathways between inflammation and carotid atherosclerosis: high GlycA was associated with CAP whereas high CRP was more associated with obesity.

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BACKGROUND: Expressing the risk of atherosclerotic cardiovascular disease (ASCVD) as percentiles of the distribution according to sex and age may provide a better perception of the risk. OBJECTIVES: To determine percentiles of the 10-year ASCVD risk distribution according to sex and age in a sample of the Brazilian population; to characterize individuals at low 10-year risk but high risk percentile. METHODS: We analyzed individuals aged 40 to 75 years who underwent routine health evaluations from 2010 to 2020. Persons with known clinical ASCVD, diabetes mellitus, chronic kidney disease, or LDL-cholesterol ≥ 190 mg/dL were excluded. The 10-year ASCVD risk was calculated by the ACC/AHA pooled cohort equations. Local polynomial regression was used to determine risk percentiles. Two-sided p-values < 0.050 were considered statistically significant. RESULTS: Our sample comprised 54,145 visits (72% male, median age [interquartile range] 48 [43, 53] years). We constructed sex-specific graphs plotting age against ASCVD risk corresponding to the 10th, 25th, 50th, 75th, and 90th percentiles. Most males up to 47 years and females up to 59 years above the 75th percentile had a 10-year risk < 5%. Individuals at low 10-year risk and risk percentile ≥ 75th had a high prevalence of excess weight and median (interquartile range) LDL-cholesterol levels 136 (109, 158) mg/dL (males) and 126 (105, 147) mg/dL (females). CONCLUSIONS: We established ASCVD risk percentiles according to sex and age in a large sample of the Brazilian population. This approach may increase risk awareness and help identify younger persons at low 10-year risk who may benefit from more aggressive risk factor control.

FUNDAMENTO: Expressar o risco de doença cardiovascular aterosclerótica (DCVA) em percentis da distribuição por sexo e idade pode proporcionar uma melhor percepção do risco. OBJETIVOS: Determinar os percentis da distribuição do risco de DCVA em 10 anos segundo sexo e idade em uma amostra da população brasileira; caracterizar indivíduos com baixo risco em 10 anos, mas em alto percentil de risco. MÉTODOS: Analisamos indivíduos de 40 a 75 anos que realizaram avaliações de saúde de rotina de 2010 a 2020. Foram excluídos indivíduos com DCVA clínica conhecida, diabetes mellitus, doença renal crônica ou LDL-colesterol ≥ 190 mg/dL. O risco de DCVA em 10 anos foi calculado pelas equações das coortes agrupadas do American College of Cardiology/American Heart Association. Foi utilizada a regressão polinomial local para determinar os percentis de risco. Valores de p bilateral < 0,050 foram considerados estatisticamente significativos. RESULTADOS: Nossa amostra incluiu 54.145 atendimentos (72% do sexo masculino, idade mediana [intervalo interquartil] 48 [43; 53] anos). Construímos gráficos específicos por sexo traçando a idade contra o risco de DCVA correspondente aos percentis 10, 25, 50, 75 e 90. A maioria dos homens até 47 anos e mulheres até 59 anos acima do percentil 75 apresentaram risco em 10 anos < 5%. Indivíduos com baixo risco em 10 anos e percentil de risco ≥ 75 apresentaram alta prevalência de excesso de peso e níveis medianos (intervalos interquartis) de LDL-colesterol de 136 (109; 158) mg/dL (sexo masculino) e 126 (105; 147) mg/dL (sexo feminino). CONCLUSÕES: Estabelecemos percentis de risco de DCVA segundo sexo e idade em uma grande amostra da população brasileira. Essa abordagem pode aumentar a conscientização sobre o risco e ajudar a identificar pessoas mais jovens com baixo risco em 10 anos que podem se beneficiar de um controle mais agressivo dos fatores de risco.

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Background: The digitization of the primary care system provides an opportunity to evaluate the current use of statins in secondary prevention populations (myocardial infarction or stroke). Methods: We conducted a cross-sectional study (ClinicalTrials.gov, NCT05285085), analysing anonymised data routinely collected by community health workers (CHW) in Brazil between May 2016 and September 2021 to assess the proportion of self-reported statins use and associated factors. Findings: From the 2,133,900 individuals on the database, 35,103 (1.6%), mean age 66.2 years (SD14.6), 49.5% (17,382/35,103) male sex, 50.5% (17,721/35,103) female sex, and 29.6% (10,381/34,975) Caucasians, had a previous myocardial infarction (MI) (n = 11,628; 33.1%) or stroke (n = 25,925; 73.9%). Approximately 50% (17,020/35,103) were from the Northeast region, 78.7% (27,605) from urban zones, and 39.4% (13,845) with social development index (SDI) >0.7. Overall, 6.7% (2346) and 0.6% (212) reported statins and high dose statins use, respectively. Age over 60 years old (OR 1.32 [95% CI 1.19-1.47), living in the Southern region (OR 4.53 [95% CI 3.66-5.60]), having a previous diagnosis of MI (OR 4.53 [95% CI 3.66-5.60]), heart failure (OR 2.29 [95% CI 1.13-1.47]), diabetes (OR 1.50 [95% CI 1.37-1.64]), dyslipidaemia (OR 2.90 [95% CI 2.55-3.29]), chronic kidney disease (OR 1.27 [95% CI 1.08-1.48]) and use of anti-hypertensives (OR 5.47 [95% CI 4.60-6.47]) were associated with statin use. Interpretation: The analysis of a real-world database from a digitized primary care system, allowed us to identify a very low use of statins in secondary prevention Brazilian patients, mostly influenced by socio-demographic factors and co-morbidities. Funding: Novartis Biociências, Brazil.