A UK multicentre audit of the management of patients with primary hypercholesterolaemia or mixed dyslipidaemia with bempedoic acid against published lipid-lowering treatment targets.

Background: Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, was introduced to UK practice via a pre-reimbursement access scheme for adults with primary hypercholesterolaemia or mixed dyslipidaemia who are at high risk of cardiovascular disease, in whom statins are either not tolerated or contraindicated, who have not achieved target cholesterol, despite being on ezetimibe therapy, and do not qualify for PCSK9 inhibitor treatment. This retrospective multicentre audit aimed to evaluate the achievement of lipid-lowering targets with bempedoic acid in UK patients based on recommendations in the Joint British Societies (JBS) guidelines for the prevention of cardiovascular disease. Methods: Pseudo-anonymized medical record data for 221 adults treated with bempedoic acid as part of the UK scheme were entered into a bespoke data collection tool at four UK hospitals. Patient demographics, clinical characteristics, treatment pathways and lipid assessment results (against JBS lipid-lowering targets) were collected against pre-specified criteria. Results: Overall, 54% (99/184) of patients achieved the JBS2 audit standard (total cholesterol (TC) <5 mmol/L and low-density lipoprotein cholesterol (LDL-C) <3 mmol/L or ≥25% reduction in TC and ≥30% reduction in LDL-C) at 12 weeks post-initiation. At week 12, the mean absolute change in LDL-C was -1.0 mmol/L; the mean percentage reduction from baseline was 22.0%. Additionally, 52% (96/185) of patients had an LDL-C of <3 mmol/L and 10% (18/185) an LDL-C of <1.8 mmol/L at 12 weeks (as per JBS3). Conclusion: This audit highlights the role of bempedoic acid as part of combination therapy for a population with previously limited treatment options.

Time-course atherogenic blood lipid response to statin discontinuation in dyslipidemic adults.

BACKGROUND AND AIMS: Half of dyslipidemic patients sometimes discontinue statin medication. It is unclear if blood atherogenic risk increases right after statin discontinuation or if there is a lingering protective effect. We sought to determine if a legacy effect prevented blood lipid increases during the first stages of statin cessation. METHODS AND RESULTS: Atherogenic blood lipid profile was measured in 10 overweight (BMI 31 ± 3 kg m-2) middle-aged males (62 ± 7 years old), statin users, while fasted and postprandially. Trials were conducted before (i.e., Day 0) and after 4, 7, 15, and 30 days of statin withdrawal and 20 days after statins reloading (Day 50). Four days after statin discontinuation, blood fasting LDL-c, total cholesterol (CHOL), and triglyceride (TG) concentrations increased by 30%, 18%, and 17%, respectively (P < 0.05). The increases in LDL-c, CHOL, and TG peaked after 7-15 days at 79%, 48%, and 34% of basal levels (P < 0.001), respectively. There were no significant correlations between the increases in blood lipids and the dose or years under statin treatment (P = 0.156-0.575). Twenty days after resuming statins, blood LDL-c (2.79 ± 1.06 vs 2.20 ± 0.50 mmol L-1; P = 0.568), CHOL (4.85 ± 1.41 vs 4.25 ± 0.83 mmol L-1; P = 0.747), and TG (1.47 ± 0.60 vs 1.50 ± 0.68 mmol L-1; P = 0.782), returned to basal levels. CONCLUSIONS: Our data does not support a statin lingering/legacy effect in blood lipids since they dangerously increased after only 4 days of statin withdrawal in every patient, regardless of dose and years under treatment. Reloading statins restored blood lipids, evidencing a reproducible biological effect at the whole-body level.

A Case of Anti-3-hydroxy-3-methylglutaryl-coenzyme A Reductase Myopathy Associated With Advanced Cervical Carcinoma.

BACKGROUND: Necrotizing autoimmune myopathy is characterized by skeletal muscle weakness and is frequently associated with cancer. Absence of treatment can lead to severe muscular atrophy but initial symptoms may be insidious and delay the diagnosis. Here, we describe the case of a 70-year-old woman who was diagnosed with mnti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy during chemotherapy course for cervical cancer. CASE REPORT: A 70-year-old woman received chemotherapy for an advanced cervical carcinoma. She had no other relevant medical history and did not take statins. During the treatment she presented muscle weakness and myalgia. Biological tests showed elevated creatine phosphokinase level (3750 IU/l) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies were detected in the serum. The electroneuromyogram showed short myotonic bursts in the upper limbs, with a myogenic appearance. A muscle biopsy was performed and confirmed the diagnosis of necrotizing autoimmune myopathy. The patient showed improvements after treatment with intravenous immunoglobulin and corticosteroid therapy. Then, the patient was successfully treated with subcutaneous methotrexate, which controlled the disease and demonstrated its value as maintenance treatment. CONCLUSION: This case highlights the importance of screening for rare myopathies in patients suffering from cancer with myalgias and muscle weakness and the importance of electroneuromyogram and magnetic resonance imaging in the early onset of symptoms to make the correct diagnosis.

Diagnosis of Statin-Induced Necrotizing Myopathy: Contribution of Anti-HMGCR Antibodies.

Over the last few years, several cases of statin-induced necrotizing myopathy have been described. This myopathy is characterized by the necrosis of muscle fibers and the presence of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. Although the diagnosis of myopathies relies on muscle biopsy, which is considered the gold-standard, the search for autoantibodies has proved to be an essential contribution to the diagnosis of immune-mediated myopathies. The detection of anti-HMGCR antibodies in the patient's serum can be performed by enzyme immunoassays, and more recently, by imunofluorescence. As for the latter, the detection of anti-HMGCR antibodies is performed on tissue sections by indirect immunofluorescence and is characterized by a typical fluorescence pattern called "HMGCR Associated Liver IFL Pattern". The authors present two case reports that show the importance of diagnosing statin-induced necrotizing myopathy as quickly as possible and the contribution of anti-HMGCR antibody detection for the diagnosis.

Nos últimos anos foram descritos vários casos de miopatia necrotizante induzida por estatinas. Esta miopatia caracteriza-se por necrose das fibras musculares e pela presença de anticorpos anti-3-hidroxi-3-metilglutaril-coenzima A redutase (anti-HMGCR). Apesar do diagnóstico das miopatias depender da biópsia muscular, considerada o gold-standard, a pesquisa dos auto-anticorpos tem-se revelado uma contribuição fundamental para o diagnóstico das miopatias imuno-mediadas. A pesquisa dos anticorpos anti-HMGCR no soro do doente pode ser efetuada por recurso a imunoensaios enzimáticos e mais recentemente foi descrita a possibilidade da sua deteção por imunofluorescência. Neste caso, a pesquisa de anticorpos anti-HMGCR é efetuada em seções de tecido, por imunofluorescência indireta e caracteriza-se pela deteção de um padrão de fluorescência típico denominado "HMGCR Associated Liver IFL Pattern". Os autores apresentam dois casos-clínicos que evidenciam não só a importância de diagnosticar o mais rapidamente possível a miopatia necrotizante induzida por estatinas como também a contribuição da deteção de anticorpos anti-HMGCR para o diagnóstico desta miopatia.

Uso de estatinas melhora a proteção cardiometabólica promovida pelo treinamento físico em ambiente aquático: Um ensaio clínico randomizado / Statin use improves cardiometabolic protection promoted by physical training in an aquatic environment: A Randomized Clinical Trial

Resumo Fundamento: O uso de estatinas destaca-se como a terapia mais frequentemente utilizada para o tratamento de dislipidemias e pode ser considerado a intervenção farmacológica mais eficiente para a redução da lipoproteína de baixa densidade (LDL). Por outro lado, o treinamento físico pode ser considerado uma estratégia não farmacológica eficiente e segura para promover melhorias no perfil lipídico. No entanto, não se sabe qual seria a influência das estatinas nas adaptações lipídicas decorrentes do treinamento aquático em populações com dislipidemia. Objetivos: Analisar a influência do uso de sinvastatina nas adaptações lipídicas decorrentes do treinamento aeróbico em meio aquático e de resistência em mulheres idosas com dislipidemia. Métodos: Sessenta e nove mulheres idosas (66,13 ± 5,13 anos), sedentárias e dislipidêmicas, tanto não usuárias quanto usuárias de sinvastatina (20 mg e 40 mg), foram randomizadas nos 3 grupos seguintes: treinamento aeróbico em meio aquático (WA), treinamento de força em meio aquático (WR) e grupo controle (GC). A duração total das intervenções, para todos os grupos experimentais, foi de 10 semanas, com 2 sessões semanais. As análises bioquímicas foram realizadas antes do início das intervenções e repetidas após o final do ensaio. Foram utilizadas equações de estimativa generalizada para comparar esses dados, estabelecendo α = 0,05. Resultados: Na análise por intenção de tratar, as participantes medicadas demonstraram uma redução de magnitude maior do colesterol total (CT) (−3,41 a −25,89 mg.dl−1; p = 0,038), LDL (−5,58 a −25,18 mg.dl−1; p = 0,007) e da relação CT/HDL (−0,37 a −0,61; p = 0,022) quando comparadas às participantes não medicadas, essa redução sendo estatisticamente significativa apenas no grupo WR. Conclusões: O uso de estatina incrementa as adaptações promovidas pelo treinamento físico aquático no CT, nos níveis de LDL e na relação CT/HDL, sendo mais pronunciado após WR.

Abstract Background: Statin use is highlighted as the most commonly utilized therapy for the treatment of dyslipidemias and can be considered as the most efficient pharmacological intervention for low-density lipoprotein (LDL) reduction. On the other hand, physical training can be considered an efficient and safe non-pharmacological strategy to promote improvements in lipid profile. However, the influence of statins on lipid adaptations arising from water-based training in populations with dyslipidemia is not known. Objectives: To analyze the influence of simvastatin use on lipid adaptations arising from water-based aerobics and resistance training in elderly women with dyslipidemia. Methods: Sixty-nine elderly (66.13 ± 5.13 years), sedentary, and dyslipidemic women, both non-users and users of simvastatin (20 mg and 40 mg), were randomized into the following 3 groups: water-based aerobic training (WA), water-based resistance training (WR), and control group (CG). Total duration of interventions, for all experimental groups consisted of 10 weeks, with 2 weekly sessions. Biochemical analyses were performed before the beginning of the interventions and repeated after the end of the trial. Generalized estimating equations were used to compare these data, setting α = 0.05. Results: In intention-to-treat analysis, the medicated participants obtained a greater magnitude of decrease in total cholesterol (TC) (−3.41 to −25.89 mg.dl−1; p = 0.038), LDL (−5.58 to −25.18 mg.dl−1; p = 0.007) and TC/HDL ratio (−0.37 to −0.61; p = 0.022) when compared to the non-medicated participants, and this decrease was statistically significant only in the WR group. Conclusions: Statin use enhances the adaptations promoted by water-based physical training in CT, LDL levels, and CT/HDL ratio, and it is more pronounced after WR.

Effect of Hydroalcoholic Ginger Extract on Brain HMG-CoA Reductase and CYP46A1 Levels in Streptozotocin-induced Diabetic Rats.

BACKGROUND: Patients with diabetes present with lipid disorders, including hypercholesterolemia, which can be a high-risk factor for atherosclerosis. Recently, increasing interest has been focused on anti-lipidemic function of herbal medicines, especially Zingiber officinale (known as ginger), in diabetes. However, the mechanism underlying the effect of ginger on some players involved in cholesterol homeostasis of Central Nervous System (CNS) among diabetic patients remains unclear. To our knowledge, this is the first study to investigate the effect of ginger on brain regulation of Hydroxymethylglutaryl-CoA Reductase (HMG-CoA reductase) and Cholesterol 24-hydroxylase (CYP46A1), which provides a rational model for understanding brain dyslipidemia mechanisms associated with diabetes. METHODS: Brains of rats were isolated from four groups: control, non-treated diabetic, and treated diabetic groups receiving 200 or 400 mg/kg of hydroalcoholic extracts of ginger for eight weeks. HMG-CoA reductase and CYP46A1 levels in brain homogenates were determined by western-blot technique. RESULTS: Ginger root extract caused a significant decrease in HMG-CoA reductase and an increase in CYP46A1 levels in treated diabetic groups compared to diabetic control. In comparison to diabetic group, these effects were more remarkable with 400 mg/kg concentration of ginger extract. CONCLUSION: The findings showed that ginger extract has a regulatory effect on proteins involved in cholesterol homeostasis in CNS by a significant down- and up-regulation of HMG-CoA reductase and CYP46A1 levels, respectively. It can be suggested that adding ginger to daily diet of diabetic patients has useful effects and may ameliorate diabetes complications.

PRavastatin Versus FlUVastatin After Statin Intolerance: The PRUV-Intolerance Study With Propensity Score Matching.

BACKGROUND: Limited data are available on the relapse of statin intolerance after resumption of statins. We aimed to evaluate the relapse rates of statin intolerance in patients who subsequently received pravastatin or fluvastatin and to identify associated factors. METHODS: This retrospective, propensity score-matched cohort study screened data obtained from a tertiary university hospital between 2006 and 2015. Of 8073 patients screened, 488 with statin intolerance who received pravastatin or fluvastatin with regular follow-up were enrolled. After propensity score matching of patients, 384 were finally analyzed. The primary outcome variables were relapse of statin intolerance and stopping (ie, discontinuation or switching to other statins) rate for the 2 statins. RESULTS: During the median follow-up period of 37 months, the rate of relapse of intolerance was 10.4% and 18.2% among users of pravastatin and fluvastatin, respectively (P = 0.04). However, the log-rank test showed no difference in the relapse-free rates between the 2 groups (P = 0.34). The stopping rates of the 2 statins were 36.5% and 42.2% (P = 0.30), respectively, for various reasons, including low efficacy of the drugs. After adjustment, chronic kidney disease (hazard ratio [HR] 1.83, P = 0.03) and previous creatine kinase elevation (HR 3.13, P = 0.001) were identified as independent determinants of relapse. Older age (HR 1.03, P = 0.057) and female sex (HR 1.70, P = 0.059) were associated, but not significantly, with relapse. CONCLUSION: Although a small proportion of patients taking pravastatin or fluvastatin experienced a relapse of intolerance, many patients eventually discontinued or changed these agents. Chronic kidney disease and history of creatine kinase elevation were independent determinants of relapse.

Locally applied statins as adjuvants to non-surgical periodontal treatment for chronic periodontitis: a systematic review and meta-analysis.

OBJECTIVE: This review aimed at evaluating the effects of chronic periodontitis (CP) treatment with local statins as adjuncts to scaling and root planing (SRP), compared with SRP alone or with placebo. METHODS: Electronic and hand searches were conducted in three databases to select randomized controlled trials (RCTs) comparing SRP + statins versus SRP alone. Random effects models were conducted to determine the clinical attachment level (CAL) gain as the primary outcome variable, and probing pocket depth (PPD) reduction, modified sulcus bleeding index (mSBI), and intrabony defect depth (IBD) as the secondary outcomes. RESULTS: Of the 526 papers identified, 15 articles met the criteria for inclusion in this systematic review, and 13 in the meta-analysis. The meta-analysis showed a statistically significant CAL gain (mean differences [MD] = 1.84 mm, 95% confidence interval [CI] = 1.45 to 2.23; p = 0.000), PPD reduction (MD = 1.69 mm, 95% CI = 1.37 to 2.04; p = 0.000), mSBI change (MD = 0.70, 95% CI = 0.57 to 0.84; p = 0.000), and IBD (MD = 1.48, 95% CI = 1.30 to 1.67; p = 0.000) attributed to SRP + statin treatment (6 months). CONCLUSION: Within the limitations of this study, the collective evidence emerging from this systematic review and meta-analysis may support the use of locally applied statins as adjuncts to SRP in CP treatment, based on being an easy, low-cost alternative, with lesser adverse effects on bacterial resistance. These results should be interpreted with caution. CLINICAL RELEVANCE: Clinicians might consider the use of SRP + statins as an adjunct over other alternative approaches, based on the results of the present review. The informed decision should be taken, considering the patient's values and preferences, and the intervention to be implemented by the clinician.

Water-Soluble Fish Protein Intake Led to Lower Serum and Liver Cholesterol Concentrations in Obese Zucker fa/fa Rats.

Proteins from different fish species and different raw materials such as fish fillets and by-products have shown promising cardioprotective effects in rodents and humans, including effects on cholesterol metabolism. Blue whiting is used mainly to produce fish meal for the feed industry and during this production, a water-soluble protein fraction, containing small peptides that are easily absorbed and may hold bioactive properties, is isolated. The effects of water-soluble fish protein on cholesterol metabolism were investigated in twelve male obese Zucker fa/fa rats. Rats were fed diets with water-soluble protein from blue whiting (BWW) as 1/3 of the total protein and the remaining 2/3 as casein (BWW group) or with casein as the sole protein source (control group). After 5 weeks intervention, the BWW group had lower serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol concentrations and lower cholesteryl ester concentration compared to controls. Hepatic concentrations of cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and LDL receptors were also lower in the BWW group. The groups had a similar concentration of serum total bile acids and similar fecal excretions of cholesterol and bile acids. To conclude, the BWW diet led to lower concentrations of serum and liver cholesterol in obese Zucker fa/fa rats, probably due to lower hepatic cholesterol synthesis.

The effect of statins on periodontal treatment-a systematic review with meta-analyses and meta-regression.

OBJECTIVE: This study aimed to systematically review clinical trials about the effect of statins as adjunct to mechanical periodontal therapy, on probing pocket depth, clinical attachment level, and intrabony defects, in comparison to mechanical periodontal therapy alone or in association with placebo. MATERIAL AND METHODS: Three databases were searched for controlled clinical trials that used any locally delivered or systemically statin as a sole adjunctive therapy to mechanical periodontal treatment. Weighted mean differences between baseline and 6 months after periodontal treatment for clinical attachment level (CAL), probing pocket depth (PPD), and intrabony defect (IBD) were calculated. A high heterogeneity was detected. Therefore, a meta-regression adjusted for type of statin and year of publication was performed. RESULTS: Fifteen studies were included in the systematic review, and ten studies were included in the meta-analysis. In the meta-regression, the adjunct use of simvastatin, rosuvastatin, and atorvastatin additionally reduced PPD in comparison to mechanical periodontal therapy and a placebo gel (2.90 ± 0.35, 3.90 ± 0.77, 3.06 ± 0.71 mm, respectively; p < 0.05). Regarding the resolution of IBD, simvastatin and rosuvastatin significantly improved in comparison to control group (0.89 ± 0.35 and 1.93 ± 0.77 mm, respectively; p < 0.05). No statistically significant difference was found between the statins for both PPD and IBD (p < 0.05). Regarding CAL gain, simvastatin provided a statistically significant improvement as compared to the control group (2.02 ± 0.79 mm; p = 0.043). CONCLUSIONS: The use of statins, used as sole adjuncts to mechanical periodontal treatment, improved the periodontal parameters. In the quantitative analyses, simvastatin was the only drug that showed additional benefits in all evaluated parameters. CLINICAL RELEVANCE: Statins promote significantly clinical periodontal improvements when administered in association with non-surgical scaling and root planning (SRP), when compared to SRP alone or in association with a placebo.

Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis.

OBJECTIVE: The cellular demand for cholesterol requires control of its biosynthesis by the mevalonate pathway. Regulation of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), a rate-limiting enzyme in this pathway and the target of statins, is a key control point herein. Accordingly, HMGCR is subject to negative and positive regulation. In particular, the ability of oxysterols and intermediates of the mevalonate pathway to stimulate its proteasomal degradation is an exquisite example of metabolically controlled feedback regulation. To define the genetic determinants that govern this process, we conducted an unbiased haploid mammalian genetic screen. APPROACH AND RESULTS: We generated human haploid cells with mNeon fused to endogenous HMGCR using CRISPR/Cas9 and used these cells to interrogate regulation of HMGCR abundance in live cells. This resulted in identification of known and new regulators of HMGCR, and among the latter, UBXD8 (ubiquitin regulatory X domain-containing protein 8), a gene that has not been previously implicated in this process. We demonstrate that UBXD8 is an essential determinant of metabolically stimulated degradation of HMGCR and of cholesterol biosynthesis in multiple cell types. Accordingly, UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control. Mechanistically, we show that UBXD8 is necessary for sterol-stimulated dislocation of ubiquitylated HMGCR from the endoplasmic reticulum membrane en route to proteasomal degradation, a function dependent on its UBX domain. CONCLUSIONS: We establish UBXD8 as a previously unrecognized determinant that couples flux across the mevalonate pathway to control of cholesterol synthesis and demonstrate the feasibility of applying mammalian haploid genetics to study metabolic traits.

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.

Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes.

RATIONALE: Hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (Hrd1) is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD has been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. OBJECTIVE: The objective of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. METHODS AND RESULTS: The effects of small interfering RNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure overload-induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin and tunicamycin increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, thapsigargin and tunicamycin dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction and increased apoptosis and cardiac hypertrophy, whereas Hrd1 overexpression preserved cardiac function and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure overload. CONCLUSIONS: Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy.

Efeitos pleiotrópicos das estatinas na sepse / Pleiotropic effects of statins in sepsis

O objetivo do presente estudo foi revisar os efeitos da terapia com estatinas em pacientes com quadro de sepse. Foi realizada uma busca bibliográfica de artigos na base de dados MEDLINE/PubMed, SciELO e LILACS, no período de publicação delimitado entre 2009 e 2013. Foram incluídos artigos referentes a ensaios clínicos randomizados controlados e estudos de coorte observacionais clínicos. Foram encontrados diversos estudos clínicos e observacionais que investigaram o efeito do uso de estatinas em infecções e em sepse, tanto de uso contínuo pré-hospitalar (com ou sem interrupção durante internação) ou com início imediato pós-internação. Alguns estudos descrevem prováveis efeitos positivos e benéficos da terapia com estatinas no quadro de sepse, dentre eles a melhora dos parâmetros inflamatórios e da taxa de mortalidade, porém, esses resultados não se sustentam quando são aplicados métodos estatísticos que levamem conta diferentes variáveis, tais como idade, sexo, comorbidades e gravidade da doença. Até o momento nenhum estudo demonstrou evidências sólidas e significativas quanto à redução de mortalidadee morbidade no quadro séptico associado ao uso de estatinas, indicando que seu efeito benéfico e protetor ainda não foi plenamente delimitado, sendo necessários mais estudos que confirmem os resultados até agora encontrados.

The objective of this study was to review the effects of statin therapy in patients with signs of sepsis. A bibliographic search of articles published between 2009-2013 was performed in the MEDLINE/PubMed, SciELO and LILACS databases. Randomized controlled trials and observational clinical cohort studies were included. The results show that several clinical and observational studies have investigated the effect of statin in infection and sepsis, both pre-hospital continuous use (with or without interruption during hospitalization) or starting immediately post-hospitalization. Some studies describe positive and beneficial effects of statin therapy in the contextof sepsis, including improvement on inflammatory parameters and mortality rates. However, these results do not hold on when statistic methods, which take into account different variables such as age, sex, comorbidities and severity disease, are applied. To date, no study has demonstrated strong and significant evidence regarding the reduction of morbidity and mortality in sepsis associated with the use of statin. This indicates that beneficial and protective effects have not been fully defined yet. More researches are required to confirm the results found so far.

Statin use in giant cell arteritis: a retrospective study.

OBJECTIVE: (1) To examine the association between statin use and giant cell arteritis (GCA); (2) to compare the clinical features and disease course of GCA among statin users and nonusers. METHODS: For this retrospective study, we reviewed the medical records of all patients with biopsy-positive GCA diagnosed between 1998 and 2008. Using a case-control design, we compared the frequency of statin use in GCA patients to non-GCA population-based subjects who were randomly selected and individually matched by sex, age, and calendar year to the GCA cases. Statin use at diagnosis or index date and during followup was abstracted. In subjects with GCA, clinical information at diagnosis and followup was collected. RESULTS: We included 594 patients, 297 with GCA (73% female), mean age at diagnosis 75 years. The rate of statin exposure at index date was 18.1% for GCA patients versus 33.3% for controls (p < 0.001). Patients using statins were less likely to develop GCA compared with patients not using statins (OR 0.31, 95% CI 0.15-0.6, p < 0.001), even after adjustment for cardiovascular risk factors. Among patients with GCA, the presenting clinical features and acute-phase reactants were similar in patients receiving statins compared to those not on statin therapy. These 2 groups were also similar with regard to relapse rate, prednisone tapering, and overall survival. CONCLUSION: Patients using statins may be less likely to develop GCA compared to patients who are not using statins. Statin use does not appear to modify the clinical presentation or the course of the disease.

Uso crônico e regular de estatina previne fibrilação atrial no pós-operatório de cirurgia cardíaca / Chronic and regular use of statin prevents atrial fibrillation in period after cardiac surgery

FUNDAMENTO: Fibrilação atrial é uma complicação frequente no pós-operatório de cirurgia cardíaca. O uso prévio de estatinas pode reduzir a incidência dessa arritmia. OBJETIVO: Avaliar se o uso crônico e regular de estatina, por um período de seis meses, previne fibrilação atrial no pós-operatório de cirurgia cardíaca eletiva. MÉTODOS: Estudo realizado em 107 pacientes submetidos à cirurgia cardíaca, 66 por cento do sexo masculino e com idade média de 60,4 anos (25 a 84). Avaliou-se a presença de fibrilação atrial entre os pacientes que usavam ou não estatina de forma regular no pré-operatório. Foram excluídos pacientes com cirurgia cardíaca de urgência, insuficiência renal, doenças inflamatórias, fibrilação atrial prévia, portadores de tireoidopatia e aqueles em uso de marca-passo definitivo. RESULTADOS: No período pós-operatório, fibrilação atrial esteve presente em 42 pacientes (39 por cento) da amostra, sendo 11 (26 por cento) em uso regular de estatina no período pré-operatório e 31 (74 por cento) não. Observou-se que, em 22 por cento do total de pacientes em uso de estatina, não houve desenvolvimento de fibrilação atrial, enquanto 45 por cento dos que não usavam estatina apresentaram arritmia (ρ=0,02). Na revascularização miocárdica isolada, 47 por cento dos pacientes que não usavam estatina e 23 por cento dos que usavam desenvolveram fibrilação atrial (ρ =0,02). Não houve diferença estatística significativa na análise dos grupos com ou sem estatina quanto à presença dos fatores de risco para desenvolvimento de fibrilação atrial ( ρ=0,34). CONCLUSÃO: O uso regular de estatina, por seis meses ou mais no período pré-operatório, reduziu a incidência de fibrilação atrial no pós-operatório de cirurgia cardíaca eletiva.

BACKGROND: Atrial fibrillation is a common complication after cardiac surgery. The previous use of statins may reduce the incidence of this arrhythmia. OBJECTIVE: To evaluate whether the chronic and regular use of statins, for a period of six months, prevents atrial fibrillation after elective cardiac surgery. METHODS: A study carried out with 107 patients that underwent cardiac surgery, including 66 percent of males and their mean age was 60.4 years (25 to 84). We evaluated the presence of atrial fibrillation among patients that used statins or not on a regular basis in the preoperative period. We excluded patients with urgent heart surgery, kidney failure, inflammatory diseases, previous atrial fibrillation, patients with thyroid disease and those using a permanent pacemaker. RESULTS: In the postoperative period, atrial fibrillation was present in 42 patients (39 percent) of the sample, including 11 (26 percent) people that had used statins on a regular basis in the preoperative period and 31 (74 percent) who had not. It was possible to observe that, in 22 percent of the patients that were using statin, there was no development of atrial fibrillation, while 45 percent of those who did not take statin had arrhythmia (ρ = 0.02). In the isolated myocardial revascularization, 47 percent of the patients that did not take statin and 23 percent of those that took statin developed atrial fibrillation ( ρ = 0.02). There was no statistically significant difference in the analysis of groups with or without statin for the presence of risk factors for the development of atrial fibrillation (ρ = 0.34). CONCLUSION: The regular use of statin, for six months or more in the preoperative period, reduced the incidence of atrial fibrillation after elective cardiac surgery.