Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that are highly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drug metabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

MicroRNAs hsa-miR-618 and hsa-miR-297 Might Modulate the Pleiotropic Effects Exerted by Statins in Endothelial Cells Through the Inhibition of ROCK2 Kinase: in-silico Approach.

Several studies show that statin therapy improves endothelial function by cholesterol-independent mechanisms called "pleiotropic effects." These are due to the inhibition of the RhoA/ROCK kinase pathway, its inhibition being an attractive atheroprotective treatment. In addition, recent work has shown that microRNAs, posttranscriptional regulators of gene expression, can affect the response of statins and their efficacy. For this reason, the objective of this study was to identify by bioinformatic analysis possible new microRNAs that could modulate the pleiotropic effects exerted by statins through the inhibition of ROCK kinases. A bioinformatic study was performed in which the differential expression of miRNAs in endothelial cells was compared under two conditions: Control and treated with simvastatin at 10 µM for 24 h, using a microarray. Seven miRNAs were differentially expressed, three up and four down. Within the up group, the miRNAs hsa-miR-618 and hsa-miR-297 present as a predicted target to ROCK2 kinase. Also, functional and enriched pathway analysis showed an association with mechanisms associated with atheroprotective effects. This work shows an in-silico approach of how posttranscriptional regulation mediated by miRNAs could modulate the pleiotropic effects exerted by statins on endothelial cells, through the inhibition of ROCK2 kinase and its effects.

Pleiotropic effects of statins on brain cells.

Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual crosstalk between the two cell types, particularly the transport of cholesterol from its site of synthesis to its target loci in neuronal cells, discussing the multiple mechanistic aspects and transporter systems involved. Statins are next analyzed from the point of view of their chemical structure and its impingement on their pharmacological properties and permeability through cell membranes and the blood-brain barrier in particular. The following section then discusses the transcriptional effects of statins and the changes they induce in brain cell genes associated with a variety of processes, including cell growth, signaling and trafficking, uptake and synthesis of cholesterol. We review the effects of statins at the cellular level, analyzing their impact on the cholesterol composition of the nerve and glial cell plasmalemma, neurotransmitter receptor mobilization, myelination, dendritic arborization of neurons, synaptic vesicle release, and cell viability. Finally, the role of statins in disease is exemplified by Alzheimer and Parkinson diseases and some forms of epilepsy, both in animal models and in the human form of these pathologies.

Short- and long-term effects on reproductive parameters of female Wistar rats after exposure to rosuvastatin starting in pre-puberty.

Statins are a class of drugs that act lowering lipid levels by inhibiting cholesterol biosynthesis. Additionally, statins can act by "pleiotropic effects", related to the inhibition of synthesis of the other mevalonate pathway products. Rosuvastatin is a third-generation statin and has shown better results in reducing cholesterol concentrations when compared to other statins. Recent studies suggest that rosuvastatin may act as an endocrine disruptor that potentially damages the hormonal axis and, consequently reproductive development and function of male rats. However, the effects of rosuvastatin exposure on rat female reproductive parameters remain unknown. In this study female rats were exposed to rosuvastatin at the doses of 0 (control), 3, or 10 mg/Kg.bw-1/day from pre-puberty to adulthood. No alterations in the female reproductive parameters were observed at a dose of 3 mg/Kg.bw-1. However, females exposed to 10 mg/Kg.bw-1 exhibited shorter estrous cycles, altered copulatory behavior, decreased serum prolactin level, and alterations in the liver, pituitary and placental weights, parameters to some extent influenced by the reproductive hormonal axis signaling pathway. On the other hand, pubertal onset, reproductive hormone levels, fertility, and histological parameters of the ovary, uterus, and placenta were unaltered by exposure to both doses of this statin. Thus, rosuvastatin exposure, at the higher dose, altered the reproductive function of female rats, probably due to the pleiotropic effects of this statin. Additional studies on the effects of this statin on female reproductive function and development are encouraged to better characterize its mode of action.

Heat treatment alleviates the growth and photosynthetic impairment of transplastomic plants expressing Leishmania infantum Hsp83-Toxoplasma gondii SAG1 fusion protein.

Previously, we showed that transplastomic tobacco plants expressing the LiHsp83-SAG1 fusion protein displayed a chlorotic phenotype and growth retardation, while plants expressing the SAG1 and GRA4 antigens alone did not. We conducted a comprehensive examination of the metabolic and photosynthetic parameters that could be affecting the normal growth of LiHsp83-SAG1 plants in order to understand the origin of these pleiotropic effects. These plants presented all photosynthetic pigments and parameters related to PSII efficiency significantly diminished. However, the expression of CHLI, RSSU and LHCa/b genes did not show significant differences between LiHsp83-SAG1 and control plants. Total protein, starch, and soluble sugar contents were also greatly reduced in LiHsp83-SAG1 plants. Since Hsp90 s are constitutively expressed at much higher concentrations at high temperatures, we tested if the fitness of LiHsp83-SAG1 over-expressing LiHsp83 would improve after heat treatment. LiHsp83-SAG1 plants showed an important alleviation of their phenotype and an evident recovery of the PSII function. As far as we know, this is the first report where it is demonstrated that a transplastomic line performs much better at higher temperatures. Finally, we detected that LiHsp83-SAG1 protein could be binding to key photosynthesis-related proteins at 37 °C. Our results suggest that the excess of this molecular chaperone could benefit the plant in a possible heat shock and prevent the expected denaturation of proteins. However, the LiHsp83-SAG1 protein content was weakly decreased in heat-treated plants. Therefore, we cannot rule out that the alleviation observed at 37 °C may be partially due to a reduction of the levels of the recombinant protein.

AHAS Trp574Leu substitution in Raphanus sativus L.: screening, enzyme activity and fitness cost.

BACKGROUND: Feral radish (Raphanus sativus L.) is a problematic weed that has become resistant to acetohydroxyacid synthase (AHAS) inhibitor herbicides due to the Trp574Leu mutation. An AHAS gene mutation that causes herbicide resistance may have negative pleiotropic effects on plant fitness. This study reports the effects of the Trp574Leu mutation on AHAS activity and reproductive traits of R. sativus. RESULTS: Eight of 17 feral radish accessions presented individuals resistant to metsulfuron-methyl at 0.5% to >90.0% and all the resistant individuals analyzed showed the Trp574Leu mutation. Without herbicide selection, the AHAS activity was 3.2-fold higher in the susceptible accession than in the resistant one. The resistant accession was >9000-fold more resistant to metsulfuron-methyl and imazethapyr than the susceptible accession. Under low intraspecific competition during two growing seasons, AHAS-resistant feral radish accessions showed 22-38% and 21-47% lower seed numbers and yield per plant than the susceptible accession. CONCLUSION: This is the first report of fitness cost associated with the AHAS Trp574Leu mutation in R. sativus populations. This fitness cost could reduce frequency of the resistant allele without herbicide selection. © 2018 Society of Chemical Industry.

Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases.

Tendencias actuales del uso de las estatinas en dislipidemias y otros efectos extralipídicos / Current trends of the use of statins for dyslipidemias and other extra lipid effects

Introducción: Los pacientes con afecciones ateroscleróticas suelen presentar concentraciones intermedias de colesterol unido a lipoproteínas de baja densidad, lo que refleja la importancia de la interacción con otros factores de riesgo. El tratamiento con estatinas mejora el pronóstico, especialmente el tratamiento intensivo, e independientemente de los valores de colesterol, lo cual hace que se deba considerar esta estrategia terapéutica como una opción y por extensión, todos los pacientes con enfermedad vascular establecida.Objetivo: Examinar las tendencias actuales en el uso terapéutico de las estatinas.Fuente de datos: se realizó una revisión bibliográfica entre 2010-2015 en las bases de datos MedLine, Hinari, Cochrane, PubMed; de revistas líderes en la publicación de temas y artículos de interés.Síntesis de los datos: Las estatinas son fármacos eficaces para disminuir la concentración de colesterol y los triglicéridos en la circulación sanguínea. Además, aumentan moderadamente el colesterol unido a lipoproteínas de alta densidad y disminuyen la incidencia de enfermedad cardiovascular aterosclerótica, por lo que se las considera medicamentos de primera elección en el tratamiento de la dislipemia aterogénica. Se ha demostrado que el tratamiento hipolipemiante con estatinas, evita la progresión de la enfermedad hacia el episodio agudo.Conclusiones: Se actualizó que el efecto de las estatinas juega un papel fundamental en los pacientes con arteriopatía. Es conveniente iniciar el tratamiento lo más precoz posible y extenderlo a sectores arteriales como el cerebrovascular y el periférico(AU)

Introduction: Patients with acute atherosclerotic conditions usually present with moderate cholesterol concentrations together with low-density lipoprotein levels, which indicates the importance of the interactions with other risk factors. Statin therapy improves prognosis after the occurrence of an acute coronary syndrome, especially in intensive care and regardless of cholesterol values, which leads to consider this therapeutic strategy as an option to be extended to all the patients with a set vascular disease.Objective: To examine the present tendencies in the statin therapy.Data sourse: A literature review was made from 2010 to 2015 in MedLine Hinari, Cochrane and PubMed databases and in leading journals in the publication of topics and articles of interest.Data synthesis: Statins are effective drugs to decrease the blood cholesterol and triglyceride levels. Besides, they increase the high density lipoprotein cholesterol and reduce the incidence of atherosclerotic cardiovascular disease, therefore, they are considered first-choice drugs for the treatment of atherogenic dyslipidemia. It has been proved that hypolipidemic treatment with statin avoids the progression of the disease into the acute stage.Conclusions: The review provides an update on the fundamental role of statins in the treatment of patients with artheropathy. It is desirable to initiate the treatment as early as possible and to extend it to other arterial areas such as cerebrovascular and peripheral ones(AU)

Tendencias actuales del uso de las estatinas en dislipidemias y otros efectos extralipídicos / Current trends of the use of statins for dyslipidemias and other extra lipid effects

Introducción: Los pacientes con afecciones ateroscleróticas suelen presentar concentraciones intermedias de colesterol unido a lipoproteínas de baja densidad, lo que refleja la importancia de la interacción con otros factores de riesgo. El tratamiento con estatinas mejora el pronóstico, especialmente el tratamiento intensivo, e independientemente de los valores de colesterol, lo cual hace que se deba considerar esta estrategia terapéutica como una opción y por extensión, todos los pacientes con enfermedad vascular establecida. Objetivo: Examinar las tendencias actuales en el uso terapéutico de las estatinas. Fuente de datos: se realizó una revisión bibliográfica entre 2010-2015 en las bases de datos MedLine, Hinari, Cochrane, PubMed; de revistas líderes en la publicación de temas y artículos de interés. Síntesis de los datos: Las estatinas son fármacos eficaces para disminuir la concentración de colesterol y los triglicéridos en la circulación sanguínea. Además, aumentan moderadamente el colesterol unido a lipoproteínas de alta densidad y disminuyen la incidencia de enfermedad cardiovascular aterosclerótica, por lo que se las considera medicamentos de primera elección en el tratamiento de la dislipemia aterogénica. Se ha demostrado que el tratamiento hipolipemiante con estatinas, evita la progresión de la enfermedad hacia el episodio agudo. Conclusiones: Se actualizó que el efecto de las estatinas juega un papel fundamental en los pacientes con arteriopatía. Es conveniente iniciar el tratamiento lo más precoz posible y extenderlo a sectores arteriales como el cerebrovascular y el periférico(AU)

Introduction: Patients with acute atherosclerotic conditions usually present with moderate cholesterol concentrations together with low-density lipoprotein levels, which indicates the importance of the interactions with other risk factors. Statin therapy improves prognosis after the occurrence of an acute coronary syndrome, especially in intensive care and regardless of cholesterol values, which leads to consider this therapeutic strategy as an option to be extended to all the patients with a set vascular disease. Objective: To examine the present tendencies in the statin therapy. Data sourse: A literature review was made from 2010 to 2015 in MedLine Hinari, Cochrane and PubMed databases and in leading journals in the publication of topics and articles of interest. Data synthesis: Statins are effective drugs to decrease the blood cholesterol and triglyceride levels. Besides, they increase the high density lipoprotein cholesterol and reduce the incidence of atherosclerotic cardiovascular disease, therefore, they are considered first-choice drugs for the treatment of atherogenic dyslipidemia. It has been proved that hypolipidemic treatment with statin avoids the progression of the disease into the acute stage. Conclusions: The review provides an update on the fundamental role of statins in the treatment of patients with artheropathy. It is desirable to initiate the treatment as early as possible and to extend it to other arterial areas such as cerebrovascular and peripheral ones(AU)

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II-induced microcirculatory changes in a model of primary hypertension.

OBJECTIVE: We investigated the acute effects of SIM on cerebral microvascular rarefaction and dysfunction in SHRs. METHODS: Male WKY and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with SIM (30 mg/kg/d) for 3 days by gavage. Cerebral FCD was assessed by intravital fluorescence videomicroscopy. mCBF before and after administration within the cranial window of angiotensin II (1 µmol L-1 ) was investigated using laser speckle contrast imaging. RESULTS: Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (P < .05). SIM increased cerebral FCD in SHRs compared to SHR-CTL (P < .05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (P < .05), and SIM increased mCBF compared with SHR-CTL (P < .05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY-CTL (SHR-CTL -13.53 ± 2% vs WKY-CTL +13.74 ± 4%; P < .001), which was attenuated in SHRs treated with SIM (SHR+SIM -6.7 ± 1% vs SHR-CTL -13.53 ± 2%; P < .01). CONCLUSIONS: The antihypertensive effect of SIM is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol-lowering.

Effects of clopidogrel on inflammatory cytokines and adhesion molecules in human endothelial cells: Role of nitric oxide mediating pleiotropic effects.

INTRODUCTION: Clopidogrel is commonly used in prevention and treatment of atherothrombosis. Some previous studies have suggested a pleiotropic effect of clopidogrel; however, when this drug causes platelet-independent effects on endothelial function remains unclear. AIMS: To evaluate the influence of clopidogrel on inflammatory biomarkers and adhesion molecules in human endothelial cells and the role of nitric oxide (NO) in this process. METHODS: TNF-α-induced human umbilical vein endothelial cells (HUVEC) were exposed to clopidogrel. Gene expression and protein expression of ICAM-1, P-selectin, IL-8, IL-6, and MCP-1 were evaluated by qPCR, flux cytometry, or milliplex technology. Expression of endothelial nitric oxide synthase (NOS3) and NO release were also evaluated. Influence of clopidogrel was further evaluated in NOS3 downregulated HUVEC by RNAi. RESULTS: Clopidogrel at 20 µmol/L induced NO release in HUVEC after 24-hours treatment. Gene expressions of inflammatory markers IL-8 and MCP1 were reduced after clopidogrel treatment (P<.05); however, only MCP-1 remained reduced at protein level. IL-6 was not modified by clopidogrel treatment. Gene expression and protein expression of ICAM-1 were diminished by 24-hours clopidogrel exposure, whereas P-selectin was not modified. NOS3 downregulated HUVEC model revealed that ICAM-1 modification by clopidogrel is dependent of this via, whereas MCP-1 is modulated in an NO-independent form. CONCLUSIONS: Our results support new evidence for pleiotropic effects of clopidogrel on inflammation and endothelial function. Reduction in ICAM-1 and MCP-1 in human endothelium is an important extent of the use of this drug for treatment of cardiovascular diseases, and NO has an important role in this process.

Fitness costs and stability of Cry1Fa resistance in Brazilian populations of Spodoptera frugiperda.

BACKGROUND: The presence of fitness costs of resistance to Bacillus thuringiensis (Bt) insecticidal proteins in insect populations may delay or even reverse the local selection of insect resistance to Bt transgenic crops, and deserves rigorous investigation. Here we assessed the fitness costs associated with Cry1Fa resistance in two strains of fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), derived from field collections in different Brazilian regions and further selected in the laboratory for high levels of resistance to Cry1Fa using leaves of TC1507 corn. RESULTS: Fitness components were compared using paired resistant and susceptible strains with similar genetic backgrounds and F1 generations from reciprocal crosses, all of them reared on non-transgenic corn leaves. No apparent life history costs in the larval stage were observed in the Bt-resistant strains. Moreover, the resistance remained stable for seven generations in the absence of selection, with no decrease in the proportion of resistant individuals. Larval respiration rates were also similar between resistant and susceptible homozygotes, and heterozygotes displayed respiration rates and demographic performance equal or superior to those of susceptible homozygotes. CONCLUSION: In combination, these results indicate the lack of strong fitness costs associated with resistance to Cry1Fa in the fall armyworm strains studied. These findings suggest that Cry1Fa resistance in S. frugiperda populations is unlikely to be counterselected in Cry1Fa-free environments. © 2016 Society of Chemical Industry.

Heparin: 100 years of pleiotropic effects.

Heparin is a glycosaminoglycan with anticoagulant properties and antiinflammatory effects. The discovery of heparin approaches its 100th year and its antiinflammatory properties still draws much attention and anticipation to new possibilities of use and the likelihood of developing heparin-like drugs that lacked the anticoagulation effects. It is known that heparins limit the embolization and the extension of the thrombus, although they do not promote its complete lysis in most cases. The complexity and pleiotropic characteristics of these glycosaminoglycans still challenge science, to the point in which approaches hitherto unusual appear repeatedly in the literature. New indications, accompanied by longtime consecrated others, dismantle the idea of an outdated medication and create high expectations for the near future. The objective of this review is to analyze the pleiotropic effects of heparin and its use in several diseases, highlighting its safety and effectiveness.

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ± 0,01 vs. 0,62 ± 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ± 0,024 vs. 0,208 ± 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ± 0,022 vs. 0,32 ± 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.(AU)

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ± 0.01 vs. 0.62± 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ± 0.024 vs. 0.208 ± 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ± 0.022 vs. 0.32± 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.(AU)

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ñ 0,01 vs. 0,62 ñ 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ñ 0,024 vs. 0,208 ñ 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ñ 0,022 vs. 0,32 ñ 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.(AU)

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ñ 0.01 vs. 0.62ñ 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ñ 0.024 vs. 0.208 ñ 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ñ 0.022 vs. 0.32ñ 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.(AU)

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ± 0,01 vs. 0,62 ± 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ± 0,024 vs. 0,208 ± 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ± 0,022 vs. 0,32 ± 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ± 0.01 vs. 0.62± 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ± 0.024 vs. 0.208 ± 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ± 0.022 vs. 0.32± 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.