Pleiotropic effects of statins may improve outcomes in atherosclerotic renovascular disease

BACKGROUNDAtherosclerotic renovascular disease (ARD) coexists with arterial obstructive disease in the coronary, cerebral, and peripheral arteries that may remain underdiagnosed and untreated.METHODSThis retrospective study compares overall survival and renal survival (i.e., time to doubling of serum creatinine or end-stage renal disease (ESRD)) over an 11-year period in 104 ARD patients of whom 68 received statin therapy (group S) because of elevated lipid levels and 36 had no statin (group NS) because of normal lipid profile at entry.RESULTSAtherosclerosis in another vascular bed was documented in 84%. Lipid profiles at end point were virtually identical in both the groups Group S had mean survival 123 months (confidence interval (CI) 113-134) with four deaths, and mean renal survival 122 months (CI 113-131). Group NS had mean survival 33 months (CI 23-42) with 13 deaths, and mean renal survival 27 months (CI 17-37).CONCLUSIONSStatin therapy was associated with lesser rate of progression of renal insufficiency (with 7.4% of S patients reaching renal end points vs. 38.9% of NS patients) and lower overall mortality (5.9% in S vs. 36.1% in NS patients), P < 0.001 for both. Although both groups received what was deemed optimal therapy, they did have other differences that may have affected the outcomes (a limitation addressed by Cox multiple regression analysis). These results suggest the need for prospective randomized controlled studies in ARD patients in order to explore potential benefits of statins that may not be attributable solely to lipid lowering.

Effect of Statins and Aerobic Physical Exercise on Liver Function in Dyslipidemic Rats - Morphometric Study

The present study was carried out to evaluate the effect of statins associated with physical exercise (PE) in liver cells in dyslipidemic rats through cariometry. The animals were divided into six groups: animals subjected to a hypercholesterolemic diet (HD), simvastatin, with (G1) and without (G2) physical exercise (PE); HD submitted (G3) or not (G4) to PE, and commercial food diet (F) with (G5) and without (G6) PE. Histological analysis of the liver was performed by staining the slides with hematoxylin and eosin. The cariometric study included measuring the major and minor diameters of the hepatocytes nuclei. The Shapiro-Wilk test was also performed. To determine the differences among the groups, the Kruskal-Wallis Test with Dunn's post-test were conducted. The significance level was set at 5%. No difference was found in the hepatocytes nuclei between G5 and G6. When these groups were related with G3 and G4, reduced nuclei were observed. There was no difference between G1 and G6. The comparison between G6 and G2 showed that the nuclei in G2 were smaller. No difference was detected between G5 and G1. Changes were observed in the nuclei shape in G2 in comparison to G1. Considering G2 and G3, a decrease in the size of nuclei was observed in G3. On the other hand, G2 showed changes in shape in the comparative analysis with G4. The size and shape of G1 nuclei were larger than G3 as well as changes in shape were observed when compared to G4. G4 showed smaller nuclei than G3. Therefore, F, associated or not with the practice of PE, does not alter the size and shape of the hepatocytes nuclei; HD combined with sedentarism influences changes in the morphometric parameters of hepatocytes; and the association of simvastatin and PE seems to protect the hepatocytes nuclei with regard to HD.

Treatment of Dyslipidemia with Statins and Physical Exercises: Recent Findings of Skeletal Muscle Responses

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Effects of Statin and Aerobic Physical Exercise Association in the Cardiomyocytes of the Rat. Morphometric Study

Physical exercise and statins, recommended interventions to dyslipidaemia treatment, are independently related to cardiomyocytes alterations, characterized by miocardic hypertrophy and apoptosis, respectively. Thus, the objective of the present study was to analyze the effects of statin and aerobic physical exercise association in the morphometric parameters of cardiac cell nucleus. 40 male rats adults were divided into four groups: exercised (DE); sedentary (DS), exercised and statin use (DES); sedentary and statin use (DSS). The animals received during the whole experimental period a hiperlipidic diet added 20% of coconut oil and 1.25% of cholesterol; after 30 days of its ingestion, a blood collection was made to verify the dyslipidaemia. Simvastatin (20 mg) was taken five days a week, during eight weeks. During this period, the animals exercised 60 minutes daily in the treadmill. After the last day of the protocol, the cardiac muscle was collected and maintained in liquid nitrogen (-180 degrees C); the cuts were stained by Hematoxilin-Eosin method, and the cardiac fibers were submitted to the nuclear morphometric analyses. The data were analyzed using descriptive analyses, paired T test, Kruskal-Wallis test and Dunn post hoc test; for all analyses, it was adopted p<0.05. It was verified that the group receiving statin presented values statistically significant in comparison to the other groups, in the tridimensional and linear variables. The exercised and statin group, the values obtained in the morphometric analyses were similar to the control group. It is suggested that statins alone can cause alterations in the nucleus of cardiac cells that can be related to apoptosis occurrence and, when exercise is practiced associated to statin administration, the effects of statin can be reduced, what can be related to beneficial adaptations of cardiac mitochondrial in response to physical exercise, turning them more resistant to apoptotic stimuli.

Muscle response to the association of statin and physical exercise in rats

Physical exercise and statins, which are recommended for the treatment of dyslipidemia, are independently associated to the occurrence of muscle injury. The objective is analyze the effect of aerobic exercise associated to the use of simvastatin on the morphology of the gastrocnemius muscle. Thirty Wistar rats were divided into six groups, two of which received a standard diet (1 sedentary and 1 exercised) and four (1 sedentary with medication, 1 sedentary without medication, 1 exercised with medication, 1 exercised without medication) received a hypercholesterolemic diet (standard diet with the addition of cholesterol and coconut oil). Simvastatin (20 mg/Kg) was administered five days a week for eight weeks, together with aerobic training on a treadmill (9.75 m/min) for 60 minutes a day. The gastrocnemius muscle was removed, sliced, stained with Hematoxylin-Eosin and submitted to a histochemical reaction to determine mitochondrial activity. The data were analyzed using a paired t-test, analysis of variance and Scheffe's post hoc test (p<0.05). Greater histological alterations were found in the medicated and exercised animals, with a greater frequency of occurrence as well. The histochemical analysis revealed that the medicated groups had fibers with more intensive mitochondrial activity alongside fibers with an absence of reaction. The morphometric analysis revealed no significant differences between groups. It is suggested that simvastatin is a medication that leads to the occurrence of muscle injury and its administration in association with physical activity may exacerbate these injuries. This finding may be related to cellular respiration.

Efeito do exercício físico e estatinas na função muscular em animais com dislipidemia

As estatinas são utilizadas no tratamento das dislipidemias, com grande tolerância; no entanto, vários efeitos colaterais podem surgir, destacando-se miopatia. A prática regular do exercício físico (EF) produz modificações favoráveis no perfil lipídico; entretanto, pode gerar lesões musculares. OBJETIVO: Avaliar o efeito da associação entre exercício físico e estatinas na função muscular, pela análise histológica, em modelo experimental animal com dislipidemia. MÉTODOS: Foram utilizados 80 ratos machos Wistar, distribuídos em oito grupos, incluindo animais submetidos à dieta hipercolesterolêmica (DH), sinvastatina com (G1) e sem (G2) EF; DH e fluvastatina, com (G3) e sem EF (G4); alimentados com ração comercial (RC) na presença (G5) e ausência de (G6) EF; DH submetidos (G7) ou não (G8) a EF. A DH foi administrada por 90 dias, as estatinas e prática de EF em esteira rolante por oito semanas. Os animais foram sacrificados, e o músculo sóleo retirado para análise histológica. Aplicaram-se os testes t de Student pareado e análise multivariada, com nível significante para p < 0,05. RESULTADOS: As principais alterações histológicas encontradas foram fibras de diferentes diâmetros, atróficas, em degeneração, splitting, edema, infiltrado inflamatório. Essas alterações foram observadas em 90% dos animais do grupo G1, 80% do G2, 70% do G3, 30% do G4, 40% do G5 e 30% do G7. Nos grupos G6 e G8 identificaram-se fibras musculares com morfologia preservada. CONCLUSÕES: Na avaliação histológica muscular, a associação entre fluvastatina, sinvastatina e exercício físico acarreta alterações morfológicas com predomínio no uso da sinvastatina, variando de grau leve a grave, no músculo sóleo de ratos, induzidos pelos inibidores da HMG-CoA redutase.

Effect of simvastatin on the generation of autoantibodies against oxidized LDL and progression of atherosclerosis in rabbits

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

eNOS T-786C polymorphism affects atorvastatin-induced changes in erythrocyte membrane fluidity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Indicadores antropométricos e as doenças crônicas não transmissíveis em mulheres na pós-menopausa da região Sudeste do Brasil

OBJETIVO: avaliar a influência dos indicadores antropométricos sobre os marcadores de risco cardiovascular e metabólico para doenças crônicas não-transmissíveis em mulheres na pós-menopausa. MÉTODOS: realizou-se estudo clínico transversal, com 120 mulheres sedentárias na pós-menopausa (com idades entre 45 e 70 anos e última menstruação há, pelo menos, 12 meses). Foram excluídas as diabéticas insulino-dependentes e usuárias de estatinas ou terapia hormonal até seis meses prévios. Para avaliação antropométrica, foram obtidos peso, estatura, índice de massa corpórea (IMC=peso/altura²) e circunferência da cintura (CC). As variáveis metabólicas avaliadas foram colesterol total (CT), HDL, LDL, triglicérides (TG), glicemia e insulina, para os cálculos do índice aterogênico plasmático (IAP) e resistência insulínica (Homeostasis model assessment-insulin resistance, HOMA-IR). Na análise estatística, utilizara-se análise de variância one-way (ANOVA) e Odds Ratio (OR). RESULTADOS: os dados médios caracterizaram amostra com sobrepeso, com obesidade central e dislipidêmica. Sobrepeso e obesidade estiveram presentes em 77,1% e deposição central de gordura ocorreu em 87,3% das participantes. Os valores médios de CT, LDL e TG estavam acima do recomendável em 67,8, 55,9 e 45,8% das mulheres, respectivamente, com HDL abaixo dos valores adequados em 40,7%. Valores de CC >88 cm ocorreram em 14,8% das mulheres eutróficas, 62,5% no grupo com sobrepeso e 100% nas obesas (p>0,05). Os valores médios de IAP, TG e HOMA-IR aumentaram significativamente com o aumento do IMC e da CC, enquanto que o HDL diminuiu (p<0,05). Na presença da CC >88 cm, encontrou-se risco de 5,8 (IC95%=2,3-14,8), 2,61 (IC95%=1,2-5,78), 3,4 (IC95%=1,2-9,7) e 3,6 (IC95%=1,3-10,3) para HDL reduzido, hipertrigliceridemia, IAP elevado e resistência a insulina, respectivamente (p<0,05). O IMC >30 kg/m² associou-se apenas com HDL reduzido (OR=3,1; IC95%=1,44-6,85). CONCLUSÕES: a associação de duas medidas antropométricas (CC e IMC) foi eficiente para adequado diagnóstico de obesidade relacionada a alterações metabólicas em mulheres na pós-menopausa. Contudo, a simples avaliação da CC pode ser indicativo do risco cardiovascular e metabólico das doenças crônicas não transmissíveis.

The influence of local administration of simvastatin in calvarial bone healing in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The influence of ovariectomy, simvastatin and sodium alendronate on alveolar bone in rats

Bisphosphonates are currently used in the treatment of many diseases involving increased bone resorption such as osteoporosis. Statins have been widely used for the treatment of hypercholesterolemia and recent studies have shown that these drugs are also capable of stimulating bone formation. The purpose of this study was to evaluate thel influence of an estrogen deficient state and the effects of simvastatin and sodium alendronate therapies on alveolar bone in female rats. Fifty-four rats were either ovariectomized (OVX) or sham operated. A month later, the animals began to receive a daily dose of simvastatin (SIN - 25 mg/kg), sodium alendronate (ALN - 2 mg/kg) or water (control) orally. Thirty-five days after the beginning of the treatment, the rats were sacrificed and their left hemimandibles were removed and radiographed using digital X-ray equipment. The alveolar radiographic density under the first molar was determined with gray-level scaling and the values were submitted to analysis of variance (α = 5%). Ovariectomized rats gained more weight (mean ± standard deviation: 20.06 ± 6.68%) than did the sham operated animals (12.13 ± 5.63%). Alveolar radiographic density values, expressed as gray levels, were lowest in the OVX-water group (183.49 ± 6.47), and differed significantly from those observed for the groups receiving alendronate (sham-ALN: 193.85 ± 3.81; OVX-ALN: 196.06 ± 5.11) and from those of the sham-water group (193.66 ± 4.36). Other comparisons between groups did not show significant differences. It was concluded that the ovariectomy reduced alveolar bone density and that alendronate was efficient for the treatment of this condition.

Treatment of atherosclerotic renovascular disease

Treatment of atherosclerotic renovascular disease is controversial and revascularization is not a beneficial approach to all patients. Conditions as progressive deterioration of renal function, refractory hypertension or accelerated cardiovascular disease, especially recurrent pulmonary edema, could profit from renal angioplasty with stent placement. Surgical revascularization is a good option for patients who will need concomitant surgical corrections of abdominal aortic lesions. Treatment of all other patients must be individualized. Medical therapy is indicated for all patients with atherosclerotic renovascular disease. Observational studies pointed out to the beneficial effect of controlling blood pressure (<130/80 mm Hg), glucose and lipids profile, lifestyle modifications, specific use of platelet antiaggregant therapy, Angiotensin Conversion Enzyme Inhibitors (ACEI) and statins. All others cardiovascular risk factors must be controlled. The evaluation and management of other systemic atherosclerotic vascular lesions is important, especially coronary, carotid and abdominal aortic. This paper presents a review of evidences to rationale the atherosclerotic renovascular disease treatment. © 2008 Bentham Science Publishers Ltd.

Caracterização do tratamento medicamentoso com estatinas em unidade básica de saúde

Study Model: Retrospective study. Study Objective: To characterize statin treatment management due to lipid alterations and side effects throughout statin treatment in basic healthcare unit. Methods: Medical reports of women from a basic healthcare unit were analyzed, obtaining: disease presence, regular medication prescription, statin type and dosage, biochemical exams results, musculoskeletal complaints, and statin use cessation, going back the information until the medical consultation of first prescription. Results: Prescribed statins were Simvastatin and Atorvastatin at low doses (10-20 mg). Dose (48,4%) and/or type (25,4%) alterations occurred for lipid profile adequacy. Lipid levels were reduced without creatine kinase elevation. Treatment withdrawn (30,6%) was mainly due to their own decision (74%), which was strongly associated with records of musculoskeletal complaints (Odds Ratio: 6,40[1,53-26,78]). Conclusion: Statin treatment was effective in reducing serum lipid levels and self-reported pain was underestimated, characterizing the major limiting factor for treatment adherence.

Simvastatin treatment increases nitrite levels in obese women: Modulation by T-786C polymorphism of eNOS

Objective and Subjects: Evidence indicates an impairment of nitric oxide (NO) in obesity. Statins present pleiotropic effects independently of cholesterol-lowering, including increasing of eNOS expression and antioxidant effects. We evaluated the effects of simvastatin treatment at 45 days on circulating nitrite (NO marker) and TBARS-MDA levels in obese women without comorbidities (hypertension, diabetes and dyslipidemia). Moreover, we verified whether obese women carrying the C variant of T-786C polymorphism located in eNOS may have increased levels of nitrite after treatment compared to TT genotype. Results: After simvastatin treatment, while the plasma nitrite levels increased 42% (P = 0.0008), the TBARS-MDA levels reduced 58% (P = 0.0069). We observed increased levels of nitrite in both groups of genotypes (TT vs. TC + CC); however, rise in C-allele carriers was 60% comparing with 44% in TT. Conclusion: Our results demonstrated a restoration of nitrite levels in obese women treated with simvastatin, which is modulated by T-786C polymorphism. © 2013 Elsevier Inc. All rights reserved.

Avaliação do efeito da Sinvastatina em ratos submetidos a periodontite experimental e imunossuprimidos por Ciclosporina-A e Tacrolimus

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)