Effect of atorvastatin on muscle tissues of dermatomyositis and antisynthetase syndrome patients with dyslipidemia.

INTRODUCTION: In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an unprecedented way, the safety of atorvastatin on the muscular tissues of these patients. METHODS: Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia [6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo]. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed. RESULTS: In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I. CONCLUSION: Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.

[Severe rhabdomyolysis associated with atorvastatin. Case report]. / Rabdomiólisis severa asociada a atorvastatina. Reporte de caso.

Background: Dyslipidemia is a risk factor for the development of atherosclerosis and ischemic heart disease. Statins are safe drugs that are part of the routine treatment in patients with Acute Myocardial Infarction (AMI), however, rhabdomyolysis associated with severe myonecrosis due to statins can occur and associated complications such as acute kidney injury increase mortality. The main objective of this article is to report the case of a critically ill patient with AMI who presented severe statin-associated rhabdomyolysis documented with muscle biopsy. Description of the case: A 54-year-old man who presented with AMI, cardiogenic shock, and cardiorespiratory arrest requiring cardiopulmonary resuscitation, fibrinolysis, and successful salvage coronary angiography. However, he presented severe rhabdomyolysis associated with atorvastatin that required suspension of the drug and multi-organ support in a Coronary Care Unit. Conclusions: The prevalence of statin-associated rhabdomyolysis is low, however, the late elevation of CPK above 10 times its upper normal value in those patients with successful percutaneous coronary angiography should promptly draw attention, generate a diagnostic approach towards non-traumatic acquired causes of rhabdomyolysis and assess the suspension of statins.

Introducción: la dislipidemia es un factor de riesgo para el desarrollo de ateroesclerosis y cardiopatía isquémica. Las estatinas son fármacos seguros que forman parte del tratamiento de rutina en el paciente con infarto agudo de miocardio (IAM). Sin embargo, la rabdomiólisis asociada a mionecrosis severa por estatinas puede presentarse y las complicaciones asociadas como la lesión renal aguda incrementan la mortalidad. El objetivo principal de este artículo es reportar el caso de un paciente críticamente enfermo con IAM que presentó rabdomiólisis severa asociada a estatinas documentada con biopsia muscular. Caso clínico: hombre de 54 años que presentó IAM, choque cardiogénico y paro cardiorrespiratorio, que ameritó reanimación cardiopulmonar, fibrinólisis y angiografía coronaria de rescate exitosa. Sin embargo, presentó rabdomiólisis severa asociada a atorvastatina que requirió de suspensión del fármaco y soporte multiorgánico en una unidad de cuidados coronarios. Conclusiones: la prevalencia de la rabdomiólisis asociada a estatinas es baja, sin embargo, la elevación tardía de la CPK por arriba de 10 veces su valor superior normal en aquellos pacientes con angiografía coronaria percutánea exitosa debe llamar la atención, generar un abordaje diagnóstico hacia causas adquiridas no traumáticas de rabdomiólisis y valorar la suspensión de estatinas.

Alopecia Universalis after Treatment with Simvastatin and Ezetimibe: Affects on Family. / Alopecia Universal após Tratamento com Sinvastatina e Ezetimiba: Impactos na Família.

Alopecia areata (AA) is an autoimmune disease that grows in the scalp or in other parts of the body. Alopecia universalis, which is a rare form of alopecia areata, is characterized by a loss of hair that affects the entire body. In the two patients presented in this study, atorvastatin treatment was implemented, with the diagnosis of hypercholesterolemia; however, when the target values were not reached, a combination of simvastatin and ezetimibe was implemented. After a period of simvastatin/ezetimibe treatment, the AA disorder, which began with hair loss on the scalp, spread to the entire body and turned into Alopecia Universalis. Although statins can cause alopecia with autoimmune reactions, they are generally used in the treatment of alopecia due to their immunomodulatory effects.

A alopecia areata (AA) é uma doença autoimune que se desenvolve no couro cabeludo ou em outras partes do corpo. A alopecia universal, que é uma forma rara de alopecia areata, é caracterizada pela perda de pelos que afeta todo o corpo. Nos dois pacientes apresentados, o tratamento com atorvastatina foi iniciado com o diagnóstico de hipercolesterolemia, mas, quando as metas de valores não foram alcançadas, foi iniciado o tratamento com uma combinação de sinvastatina e ezetimiba. Depois de um período de tratamento com sinvastatina e ezetimiba, o distúrbio de AA, o qual começou com a perda de cabelo no couro cabeludo, espalhou pelo corpo todo e se transformou em alopecia universal. Embora as estatinas possam causar alopecia com reações autoimunes, elas geralmente são utilizadas no tratamento da alopecia, por seus efeitos imunomoduladores.

Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm.

OBJECTIVES: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA). STUDY DESIGN: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment. RESULTS: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls. CONCLUSIONS: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.

Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes.

BACKGROUND AND AIMS: Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations. METHODS: In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated. RESULTS: A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42-54) to 45 (39-56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study. CONCLUSIONS: Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux.

Atorvastatin inhibits osteoclastogenesis and arrests tooth movement.

INTRODUCTION: In addition to their cholesterol-lowering effects, the statin class of drugs appears to enhance osteogenesis and suppress bone resorption, which could be a clinical concern during orthodontic treatment. In this animal study, we aimed to determine whether atorvastatin (ATV) affects orthodontic tooth movement (OTM) through osteoclast inhibition. Furthermore, we analyzed the potential adverse effects of ATV on long-bone turnover and endochondral ossification. METHODS: Rats were administered ATV (15 mg/kg) or saline solution via gavage (n = 12 animals/group), starting 2 weeks before initial OTM. Tooth displacement was measured after 7, 14, and 21 days. Histologic sections of the maxilla and femur were obtained after 14 and 21 days of OTM and stained (hematoxylin and eosin; TRAP assay) for histomorphometric analysis. RESULTS: ATV was associated with significant (P <0.05) reductions in OTM and osteoclast counts. Independently of drug administration, OTM increased the number of osteoclasts and reduced the bone-volume ratio compared with the control maxillae without OTM. Long-term statin administration did not appear to affect femoral endochondral ossification. CONCLUSIONS: This experimental study showed that the long-term use of ATV can significantly promote osteoclast inhibition and slow the OTM in the first week in rats. Under physiologic conditions, the drug did not affect bone turnover and endochondral ossification.

Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial.

Importance: The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective: To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions: Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results: Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, -0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance: Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration: clinicaltrials.gov Identifier: NCT01448642.

High-Intensity Statin Therapy Is Associated With Improved Survival in Patients With Peripheral Artery Disease.

BACKGROUND: The relative benefit of higher statin dosing in patients with peripheral artery disease has not been reported previously. We compared the effectiveness of low- or moderate-intensity (LMI) versus high-intensity (HI) statin dose on clinical outcomes in patients with peripheral artery disease. METHODS AND RESULTS: We reviewed patients with symptomatic peripheral artery disease who underwent peripheral angiography and/or endovascular intervention from 2006 to 2013 who were not taking other lipid-lowering medications. HI statin use was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg. Baseline demographics, procedural data, and outcomes were retrospectively analyzed. Among 909 patients, 629 (69%) were prescribed statins, and 124 (13.6%) were treated with HI statin therapy. Mean low-density lipoprotein level was similar in patients on LMI versus HI (80±30 versus 87±44 mg/dL, P=0.14). Demographics including age (68±12 versus 67±10 years, P=0.25), smoking history (76% versus 80%, P=0.42), diabetes mellitus (54% versus 48%, P=0.17), and hypertension (88% versus 89%, P=0.78) were similar between groups (LMI versus HI). There was a higher prevalence of coronary artery disease (56% versus 75%, P=0.0001) among patients on HI statin (versus LMI). After propensity weighting, HI statin therapy was associated with improved survival (hazard ratio for mortality: 0.52; 95% confidence interval, 0.33-0.81; P=0.004) and decreased major adverse cardiovascular events (hazard ratio: 0.58; 95% confidence interval 0.37-0.92, P=0.02). CONCLUSIONS: In patients with peripheral artery disease who were referred for peripheral angiography or endovascular intervention, HI statin therapy was associated with improved survival and fewer major adverse cardiovascular events compared with LMI statin therapy.

Do different tendons exhibit the same response following chronic exposure to statins?

Over the past few years, a number of cases of tendon injuries associated with statin therapy have been reported. In this study, we assessed whether statins can affect the extracellular matrix (ECM) of the deep digital flexor tendon (DDFT) and patellar tendon (PT). Wistar rats were assigned to groups treated with atorvastatin (A20, A80), treated with simvastatin (S20, S80), and control. Zymography, Western blotting for collagen I, non-collagenous proteins (NCP), glycosaminoglycans (GAGs), and hydroxyproline quantifications were performed. DDFT findings: NCP were increased in A20 and A80; higher concentration of hydroxyproline was found in S80; levels of GAGs was increased in all statin-treated groups; collagen I was increased in S80 and pro-MMP-2 activity was reduced in A80, S20, and S80. PT findings: NCP were reduced in A20, A80, and S80; GAGs was reduced in A80 and S20; collagen I was increased in A20 and pro-MMP-2 activity was reduced in the S20. Both the statins provoked marked changes in both tendons. All these changes may make the tendons more prone to microdamage and ruptures. Therefore, a better understanding of the behavior of the tendon ECM components under statin therapy may provide important insights into the mechanisms behind statin-induced tendon injuries.

Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish.

BACKGROUND: Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. METHODS: We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. RESULTS: Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. CONCLUSION: Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814-830, 2016. © 2016 Wiley Periodicals, Inc.

Sintomas musculares relacionados ao uso de estatinas / Statin-associated muscle symptoms

Nas últimas duas décadas, comprovou-se que a terapia com estatinas é o instrumento isolado mais potente para atenuar o risco cardiovascular, e seu uso frequente foi enfatizado como um dos elementos mais importantes para reduzir a mortalidade cardiovascular nos países desenvolvidos. Uma incidência igualmente frequente de sintomas musculares em usuários de estatinas levanta a possibilidade de um nexo de causalidade, que leva a uma entidade patológica conhecida como sintomas musculares associados a estatinas (SMAS). Estudos e ensaios clínicos mecanicistas destinados a estudar os SMAS levaram a uma definição clara da sua história natural e incidência exata. Essa informação é essencial para evitar riscos desnecessários de formas graves de SMAS. Ao mesmo tempo, essa compreensão concreta dos SMAS evita o diagnóstico exagerado e a suspensão desnecessária de uma das mais poderosas estratégias de prevenção atuais. Nesse contexto, este artigo de revisão reuniu todas as informações disponíveis sobre o assunto, que são apresentadas em detalhe neste documento como a base da identificação e tratamento dos SMAS

In the last 2 decades, statin therapy has proved to be the most potent isolated instrument for attenuating cardiovascular risk, and its frequent use has been highlighted as one of the most important elements for reducing cardiovascular mortality in developed countries. An equally frequent incidence of muscle symptoms in statin users raises the possibility of a causal link, leading to a disease entity known as statin-associated muscle symptoms (SAMS). Mechanistic studies and clinical trials designed to the study of SAMS have led to a clear definition of its natural history and accurate incidence. This information is vital for avoiding unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents over-diagnosis and unnecessary suspension of one of the most powerful prevention strategies available today. In this context, this review has gathered all the available information on the issue, which is presented in detail, in this document, as the basis for the identification and management of SAMS

[Drug related colonic perforation: Case report]. / Perforación colónica secundaria a polifarmacia: reporte de caso.

BACKGROUND: Acute pseudo-obstruction of the colon is a disorder characterised by an increase in intra-luminal pressure that leads to ischaemia and necrosis of the intestinal wall. The mechanism that produces the lesion is unknown, although it has been associated with: trauma, anaesthesia, or drugs that alter the autonomic nervous system. The pathophysiology of medication induced colon toxicity can progress to a perforated colon and potentially death. OBJECTIVE: Present a case of a colonic pseudo-obstruction in a patient with polypharmacy as the only risk factor and to review the medical literature related to the treatment of this pathology. CLINICAL CASE: The case is presented of a 67 year old woman with colonic pseudo-obstruction who presented with diffuse abdominal pain and distension. The pain progressed and reached an intensity of 8/10, and was accompanied by fever and tachycardia. There was evidence of free intraperitoneal air in the radiological studies. The only risk factor was the use of multiple drugs. The colonic pseudo-obstruction progressed to intestinal perforation, requiring surgical treatment, which resolved the problem successfully. CONCLUSION: It is important to consider drug interaction in patients with multiple diseases, as it may develop complications that can be avoided if detected on time.