Emerging pharmacological treatments to prevent abdominal aortic aneurysm growth and rupture

Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1 beta inhibition, anti-angiogenic agents and urocortins

Estudo dos efeitos do espaço-tempo não comutativo no buraco negro de Schwarzschild

Nesse trabalho, foi feito um estudo sobre a não-comutatividade do espaço-tempo aplicada ao buraco negro de Schwarzschild. Essa teoria supõe que o espaço-tempo possui um dimensão mínima na ordem do comprimento de Planck. Uma consequência direta na Mecânica Quântica é a troca do produto entre duas funções por um produto Moyal que mantém o isomorfismo, mas traz problemas ao tentar expandir os termos desse produto, de forma que a adoção de estados coerentes se torna uma ferramenta conveniente para ser utilizada dentro do estudo de buracos negros, uma vez que podemos substituir uma massa pontual por um distribuição gaussiana, resolvendo o problema da singularidade a partir dos valores de posição média. Essa distribuição gaussiana, aplicada ao buraco negro de Schwarzschild, traz outras consequências como limites mínimos de massa e raio de horizonte de eventos necessários para a formação de um buraco negro, assim como um valor máximo de temperatura Hawking durante sua evaporação. Tais consequência não trazem inconsistências para o modelo já conhecido, pois é desprezível no nível macroscópico.In this work, a study was done about the space-time non-commutativity applied in the Schwarzschild black hole. This theory supposes a space-time with a minimal length in the Planck’s length order. A straight consequence in Quantum Mechanics is the exchange of two function product by a Moyal product, that keeps the isomorphism but brings problems when try to expand terms of this product in a way that coherent states become a convenient tool to be used in the study of black holes, since we can replace a pontual mass for a gaussian distribuction, resolving the singularity problem starting from mean values positions. This gaussian distribuction, aplied to Schwarzschild black hole, brings others consequences, like minimum limit to massa and horizon event radius necessary to a black hole formation, as a Hawking temperature maximum value during its evaporation. Such consequences do not bring inconsistencies to the already known model, because is negligible in the macroscopic level

Incidence, severity, mortality, and confounding factors for dissecting AAA detection in angiotensin II-infused mice: a meta-analysis

Aims While angiotensin II-infused mice are the most popular model for preclinical aneurysm research, representative data on incidence, severity, and mortality of dissecting abdominal aortic aneurysms (AAAs) have never been established, and the influence of confounding factors is unknown. Methods and Results We performed a meta-analysis including 194 manuscripts representing 1679 saline-infused, 4729 non-treated angiotensin II-infused, and 4057 treated angiotensin II-infused mice. Incidence (60%) and mortality (20%) rates are reported overall as well as for grade I (22%), grade II (26%), grade III (29%), and grade IV (24%) aneurysms. Dissecting AAA incidence was significantly (P < 0.05) influenced by sex, age, genetic background, infusion time, and dose of angiotensin II. Mortality was influenced by sex, genetic background, and dose, but not by age or infusion time. Surprisingly, both incidence and mortality were significantly different (P < 0.05) when comparing angiotensin II-infused mice in descriptive studies (56% incidence and 19% mortality) with angiotensin II-infused mice that served as control animals in treatment studies designed to either enhance (35% incidence and 13% mortality) or reduce (73% incidence and 25% mortality) dissecting AAA formation. After stratification to account for confounding factors (selection bias), the observed effect was still present for incidence, but not for mortality. Possible underlying causes are detection bias (non-uniform definition for detection and quantification of dissecting AAA in mice) or publication bias (studies with negative results, related to incidence in the control group, not being published). Conclusions Our data provide a new meta-analysis-based reference for incidence and mortality of dissecting AAA in angiotensin II-infused mice, and indicate that treatment studies using this mouse model should be interpreted with cautio

An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect

INTRODUCTION AND OBJECTIVE: The heptapeptide angiotensin-(1-7) is a component of the renin-angiotensin system, which promotes many beneficial cardiovascular effects, including antithrombotic activity. We have recently shown that the antithrombotic effect of angiotensin-(1-7) involves receptor Mas-mediated NO-release from platelets. Here, we describe an orally active formulation based on angiotensin-(1-7) inclusion in cyclodextrin [Ang-(1-7)- CyD] as an antithrombotic agent. Cyclodextrins are pharmaceutical tools that are used to enhance drug stability, absorption across biological barriers and gastric protection. METHOD: To test the antithrombotic effect of Ang-(1-7)-CyD, thrombus formation was induced in the abdominal vena cava of spontaneously hypertensive rats that were pretreated either acutely or chronically with Ang-(1-7)-CyD. Male Mas-knockout and wild-type mice were used to verify the role of the Mas receptor on the effect of Ang-(1-7)-CyD. RESULTS: Acute or chronic oral treatment with Ang-(1-7)-CyD promoted an antithrombotic effect (measured by thrombus weight; all values are, respectively, untreated vs. treated animals) in spontaneously hypertensive rats (acute: 2.86 + 0.43 mg vs. 1.14 + 0.40 mg; chronic: 4.27 + 1.03 mg vs. 1.39 + 0.68 mg). This effect was abolished in Mas-knockout mice (thrombus weight in Mas wild-type: 0.76 + 0.10 mg vs. 0.37 + 0.02 mg; thrombus weight in Mas-knockout: 0.96 + 0.11 mg vs. 0.87 + 0.14 mg). Furthermore, the antithrombotic effect of Ang-(1-7)-CyD was associated with an increase in the plasma level of Angiotensin-(1-7). CONCLUSION: These results show for the first time that the oral formulation Ang-(1-7)-CyD has biological activity and produces a Mas-dependent antithrombotic effect