Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System

Background:Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial.Objective:To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective.Methods:We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied.Results:Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios.Conclusions:Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil.

Role of microRNAs 221/222 on Statin Induced Nitric Oxide Release in Human Endothelial Cells

Background: Nitric oxide (NO) has been largely associated with cardiovascular protection through improvement of endothelial function. Recently, new evidence about modulation of NO release by microRNAs (miRs) has been reported, which could be involved with statin-dependent pleiotropic effects, including anti-inflammatory properties related to vascular endothelium function. Objective: To evaluate the effects of cholesterol-lowering drugs including the inhibitors of cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs potentially involved in NO bioavailability. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin, simvastatin or ezetimibe (0 to 5.0 μM). Cells were submitted to total RNA extraction and relative quantification of NOS3 mRNA and miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by ozone-chemiluminescence. Results: Both statins increased NO levels and NOS3 mRNA expression but no influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced only after the atorvastatin treatment. The magnitude of the reduction of miR-221 and miR-222 after treatment with statins correlated with the increment in NOS3 mRNA levels. No influence was observed on the miR-1303 expression after treatments. Conclusion: NO release in endothelial cells is increased by statins but not by the inhibitor of cholesterol absorption, ezetimibe. Our results provide new evidence about the participation of regulatory miRs 221/222 on NO release induction mediated by statins. Although ezetimibe did not modulate NO levels, the down-regulation of miR-221 could involve potential effects on endothelial function.

Insulin Resistance, Dyslipidemia and Cardiovascular Changes in a Group of Obese Children

Introduction: Obesity-related comorbidities are present in young obese children, providing a platform for early adult cardiovascular disorders. Objectives: To compare and correlate markers of adiposity to metabolic disturbances, vascular and cardiac morphology in a European pediatric obese cohort. Methods: We carried out an observational and transversal analysis in a cohort consisting of 121 obese children of both sexes, between the ages of 6 and 17 years. The control group consisted of 40 children with normal body mass index within the same age range. Markers of adiposity, plasma lipids and lipoproteins, homeostasis model assessment-insulin resistance, common carotid artery intima-media thickness and left ventricular diameters were analyzed. Results: There were statistically significant differences between the control and obese groups for the variables analyzed, all higher in the obese group, except for age, high-density lipoprotein cholesterol and adiponectin, higher in the control group. In the obese group, body mass index was directly correlated to left ventricular mass (r=0.542; p=0.001), the homeostasis model assessment-insulin resistance (r=0.378; p=<0.001) and mean common carotid artery intima-media thickness (r=0.378; p=<0.001). In that same group, insulin resistance was present in 38.1%, 12.5% had a combined dyslipidemic pattern, and eccentric hypertrophy was the most common left ventricular geometric pattern. Conclusions: These results suggest that these markers may be used in clinical practice to stratify cardiovascular risk, as well as to assess the impact of weight control programs.

Education to a Healthy Lifestyle Improves Symptoms and Cardiovascular Risk Factors – AsuRiesgo Study

Background: Cardiovascular diseases are the current leading causes of death and disability globally. Objective: To assess the effects of a basic educational program for cardiovascular prevention in an unselected outpatient population. Methods: All participants received an educational program to change to a healthy lifestyle. Assessments were conducted at study enrollment and during follow-up. Symptoms, habits, ATP III parameters for metabolic syndrome, and American Heart Association’s 2020 parameters of cardiovascular health were assessed. Results: A total of 15,073 participants aged ≥ 18 years entered the study. Data analysis was conducted in 3,009 patients who completed a second assessment. An improvement in weight (from 76.6 ± 15.3 to 76.4 ± 15.3 kg, p = 0.002), dyspnea on exertion NYHA grade II (from 23.4% to 21.0%) and grade III (from 15.8% to 14.0%) and a decrease in the proportion of current active smokers (from 3.6% to 2.9%, p = 0.002) could be documented. The proportion of patients with levels of triglycerides > 150 mg/dL (from 46.3% to 42.4%, p < 0.001) and LDL cholesterol > 100 mg/dL (from 69.3% to 65.5%, p < 0.001) improved. A ≥ 20% improvement of AHA 2020 metrics at the level graded as poor was found for smoking (-21.1%), diet (-29.8%), and cholesterol level (-23.6%). A large dropout as a surrogate indicator for low patient adherence was documented throughout the first 5 visits, 80% between the first and second assessments, 55.6% between the second and third assessments, 43.6% between the third and fourth assessments, and 38% between the fourth and fifth assessments. Conclusion: A simple, basic educational program may improve symptoms and modifiable cardiovascular risk factors, but shows low patient adherence.

Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression

Background:Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers.Objective:To assess the association between changes in lipid markers and regression of CPV using published data.Methods:We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV.Results:Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume.Conclusion:A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.

Changes in Medical Management after Coronary CT Angiography

AbstractIntroduction:Coronary computed tomography angiography (CCTA) allows for non-invasive coronary artery disease (CAD) phenotyping. There are still some uncertainties regarding the impact this knowledge has on the clinical care of patients.Objective:To determine whether CAD phenotyping by CCTA influences clinical decision making by the prescription of cardiovascular drugs and their impact on non-LDL cholesterol (NLDLC) levels.Methods:We analysed consecutive patients from 2008 to 2011 submitted to CCTA without previous diagnosis of CAD that had two serial measures of NLDLC, one up to 3 months before CCTA and the second from 3 to 6 months after.Results:A total of 97 patients were included, of which 69% were men, mean age 64 ± 12 years. CCTA revealed that 18 (18%) patients had no CAD, 38 (39%) had non-obstructive (< 50%) lesions and 41 (42%) had at least one obstructive ≥ 50% lesion. NLDLC was similar at baseline between the grups (138 ± 52 mg/dL vs. 135 ± 42 mg/dL vs. 131 ± 44 mg/dL, respectively, p = 0.32). We found significative reduction in NLDLC among patients with obstrctive lesions (-18%, p = 0.001). We also found a positive relationship between clinical treatment intensification with aspirin and cholesterol reducing drugs and the severity of CAD.Conclusion:Our data suggest that CCTA results were used for cardiovascular clinical treatment titration, with especial intensification seen in patients with obstructive ≥50% CAD.

Risk Factors for Cardiovascular Disease, Metabolic Syndrome and Sleepiness in Truck Drivers

Abstract Background: Truck driver sleepiness is a primary cause of vehicle accidents. Several causes are associated with sleepiness in truck drivers. Obesity and metabolic syndrome (MetS) are associated with sleep disorders and with primary risk factors for cardiovascular diseases (CVD). We analyzed the relationship between these conditions and prevalence of sleepiness in truck drivers. Methods: We analyzed the major risk factors for CVD, anthropometric data and sleep disorders in 2228 male truck drivers from 148 road stops made by the Federal Highway Police from 2006 to 2011. Alcohol consumption, illicit drugs and overtime working hours were also analyzed. Sleepiness was assessed using the Epworth Sleepiness Scale. Results: Mean age was 43.1 ± 10.8 years. From 2006 to 2011, an increase in neck (p = 0.011) and abdominal circumference (p < 0.001), total cholesterol (p < 0.001), triglyceride plasma levels (p = 0.014), and sleepiness was observed (p < 0.001). In addition, a reduction in hypertension (39.6% to 25.9%, p < 0.001), alcohol consumption (32% to 23%, p = 0.033) and overtime hours (52.2% to 42.8%, p < 0.001) was found. Linear regression analysis showed that sleepiness correlated closely with body mass index (β = 0.19, Raj2 = 0.659, p = 0.031), abdominal circumference (β = 0.24, Raj2 = 0.826, p = 0.021), hypertension (β = -0.62, Raj2 = 0.901, p = 0.002), and triglycerides (β = 0.34, Raj2 = 0.936, p = 0.022). Linear multiple regression indicated that hypertension (p = 0.008) and abdominal circumference (p = 0.025) are independent variables for sleepiness. Conclusions: Increased prevalence of sleepiness was associated with major components of the MetS.

Variations in the Prevalence of Risk Factors for Coronary Artery Disease in Rio Grande do Sul-Brazil: A Comparative Analysis between 2002 and 2014

Abstract Background: Due to the importance of coronary artery disease (CAD), continuous investigation of the risk factors (RFs) is needed. Objective: To evaluate the prevalence of RFs for CAD in cities in Rio Grande do Sul State, and compare it with that reported in a similar study conducted in the same cities in 2002. Methods: Cross-sectional study on 1,056 healthy adults, investigating the prevalence and absolute and relative frequencies of the following RFs for CAD: obesity, systemic arterial hypertension (SAH), dyslipidemias, smoking, sedentary lifestyle, diabetes mellitus, and family history, as well as age and sex. Data was collected in 19 cities, host of the Offices of the Regional Coordinators of Health, as in the 2002 study. Results: Twenty-six percent of the sample consisted of older adults and 57% were women. The prevalence of sedentary lifestyle was 44%, history family 50%, smoking 23%, overweight/obesity 68%, dyslipidemia (high cholesterol levels) 43%, SAH 40%, and diabetes 11%. When compared to the 2002 study, the prevalence of active smoking and sedentary behavior decreased, whereas the prevalence of hypertension, dyslipidemia and obesity increased. Obesity is the most prevalent RF in women, and SAH the most prevalent in men. Conclusions: The prevalence of RFs for CAD in Rio Grande do Sul State remains high. Hypertension, obesity and dyslipidemia are still prevalent and require major prevention programs. Smoking and physical inactivity have decreased in the state, suggesting the efficacy of related campaigns.

Sex Differences in High Sensitivity C-Reactive Protein in Subjects with Risk Factors of Metabolic Syndrome

Abstract Background: Metabolic syndrome (MetS) is associated with a higher risk of all-cause mortality. High-sensitivity C-reactive protein (hsCRP) is a prototypic marker of inflammation usually increased in MetS. Women with MetS-related diseases present higher hsCRP levels than men with MetS-related diseases, suggesting sex differences in inflammatory markers. However, it is unclear whether serum hsCRP levels are already increased in men and/or women with MetS risk factors and without overt diseases or under pharmacological treatment. Objective: To determine the impact of the number of MetS risk factors on serum hsCRP levels in women and men. Methods One hundred and eighteen subjects (70 men and 48 women; 36 ± 1 years) were divided into four groups according to the number of MetS risk factors: healthy group (CT; no risk factors), MetS ≤ 2, MetS = 3, and MetS ≥ 4. Blood was drawn after 12 hours of fasting for measurement of biochemical variables and hsCRP levels, which were determined by immunoturbidimetric assay. Results: The groups with MetS risk factors presented higher serum hsCRP levels when compared with the CT group (p < 0.02). There were no differences in hsCRP levels among groups with MetS risk factors (p > 0.05). The best linear regression model to explain the association between MetS risk factors and hsCRP levels included waist circumference and HDL cholesterol (r = 0.40, p < 0.01). Women with MetS risk factors presented higher hsCRP levels when compared with men (psex < 0.01). Conclusions: Despite the absence of overt diseases and pharmacological treatment, subjects with MetS risk factors already presented increased hsCRP levels, which were significantly higher in women than men at similar conditions.

Dyslipidemia is Associated with Unfit and Overweight-Obese Children and Adolescents

Abstract Background: Both poor aerobic fitness and obesity, separately, are associated with abnormal lipid profiles. Objective: To identify possible relationships of dyslipidemia with cardiorespiratory fitness and obesity, evaluated together, in children and adolescents. Methods: This cross-sectional study included 1,243 children and adolescents (563 males and 680 females) between 7 and 17 years of age from 19 schools. Obesity was assessed using body mass index (BMI) measurements, and cardiorespiratory fitness was determined via a 9-minute run/walk test. To analyze the lipid profile of each subject, the following markers were used: total cholesterol, cholesterol fractions (high-density lipoprotein and low-density lipoprotein) and triglycerides. Data were analyzed using SPSS v. 20.0, via prevalence ratio (PR), using the Poisson regression. Results: Dyslipidemia is more prevalent among unfit/overweight-obese children and adolescents compared with fit/underweight-normal weight boys (PR: 1.25; p = 0.007) and girls (PR: 1.30, p = 0.001). Conclusions: The prevalence of dyslipidemia is directly related to both obesity and lower levels of cardiorespiratory fitness.

Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe

Abstract Background: The effect of statins on the endothelial function in humans remains under discussion. Particularly, it is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial pleiotropic effect. Objective: To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered. Methods: Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group (14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment. Results: The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe (27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from 8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in LDL-cholesterol level or endothelial function. Conclusion: The improvement in endothelial function with statin seems to depend more on a reduction in LDL-cholesterol levels, independent of the dose of statin administered, than on pleiotropic mechanisms.

Early Markers of Atherosclerotic Disease in Individuals with Excess Weight and Dyslipidemia

Abstract Background: Excessive weight is a cardiovascular risk factor since it generates a chronic inflammatory process that aggravates the endothelial function. Objective: To evaluate the endothelial function in individuals with excess weight and mild dyslipidemia using brachial artery flow-mediated dilation (BAFMD), and the association of endothelial function with anthropometric and biochemical variables. Methods: Cross-sectional study that included 74 individuals and evaluated anthropometric variables (body mass index [BMI], waist-hip ratio [WHR], waist circumference [AC], and percentage of body fat [PBF]), biochemical (blood glucose, insulinemia, ultrasensitive C-reactive protein, fibrinogen, total cholesterol, HDL-cholesterol, triglycerides, and LDL-cholesterol) and endothelial function (BAFMD, evaluated by ultrasound). The statistical analysis was performed with SPSS, version 16.0. To study the association between the variables, we used chi-square, Student's t and Mann-Whitney tests, and Pearson's correlation. Logistic regression analyzed the independent influence of the factors. Values of p < 0.05 were considered significant. Results: The participants had a mean age of 50.8 years, and 57% were female. BMI, WC, WHR, and PBF showed no significant association with BAFMD. The male gender (p = 0.02) and higher serum levels of fibrinogen (p = 0.02) were significantly and independently associated with a BAFMD below 8%. Conclusions: In individuals with excess weight and mild untreated dyslipidemia, male gender and higher levels of fibrinogen were independently associated with worse BAFMD.

Lipoides do plasma normal

1. In a series of 21 normal cases we found for fatty acids per 100 cc. of plasma an average of 332 mgm., being 314 mgm. for the male sex and 350 mgm. for the female sex. 2.- For lecithin, in four normal cases we found per 100 cc. of plasma 182 mgm. estimated by the contents is phosphorus which ranged from 6.12 to 9.0 mgrs. 3.- Cholesterol in 20 normal cases showed 172 mgm. per 100 cc. of plasma. The averages were 151 mgm. for men and 194 mgm. for women. 4.- The readings of the fractions were 2.01 for the ratio fatty acids divided by lecithins 0.90 for lecithin divided by cholesterol and 1.93 for fatty acids divided by cholesterol. 5.- On comparing the results obtained by us with those reported in foreign literature an absolute conformity is noted chiefly with the values supplied by Bloor and Horiuchi for the ratios among the various lipoid fractions. The average for Cholesterol is comparable with that obtained by Myers but is slightly under that of Bloor's. The lecithin contents found by us did not reach such high values as those supplied by foreign authors.

Estudos sobre o xanthoma: biochimica e pathogenia

1. No presente trabalho são descriptos dois casos de xanthelasmatose (xanthoma) com perturbações accentuadas do metabolismo dos lipides e esteroes. 2. Um dos casos apresentou notavel cholesteroluria não mostrando o doente lesões renaes, ao passo que o outro caso sendo portador de pyelonephrite não eliminava cholesterol. 3. Foram feitas dosagens de cholesterol, acidos graxos totaes e lecithina, no sangue, urina e tumores, obtendo-se valores muito elevados. As demais provas (histo-chimicas, polarização microscopica) confirmaram a presença de abundante infiltração de lipides e cholesterol nos tecidos. 4. A prova de carga de Bürger feita no caso I demonstrou diminuição da tolerancia para o cholesterol. 5. A therapeutica insulinica fez baixar o cholesterol e a glycose do sangue sem, comtudo, offerecer melhora clinica do paciente. No caso II houve baixa da cholesterolemia e da glycemia com desapparecimento dos tumores, evidenciando a diversidade das formas clinicas destes casos. 6. A intradermo-reacção feita com o cholesterol no caso I produziu reacção positiva, suggerindo um estado de hypensensibilidade para as substancias de infiltração no xanthelasma (xanthoma). 7. Os aspectos clinico-morphologicos dos casos estudados indicam tambem a ocorrencia de processos de sensibilisação cutanea. 8. As lipidoses são encaradas neste trabalho como toxicodermias hematogenicas, sendo proposto para seu estudo os mesmos methodos de exploração cutanea.