Obesity, Adipokines, and Abdominal Aortic Aneurysm

Golledge, Jonathan; Clancy, Paula; Jamrozik, Konrad; Norman, Paul

doi:10.1161/circulationaha.107.717926

Cited by 145 publications

(173 citation statements)

References 28 publications

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“…12,21,22,24 It is hypothesised that administration of 145 mg of fenofibrate daily for 24 weeks will result in a 30% increase in serum kallistatin and a 30% reduction in serum OPN concentrations. These conservative estimates are based on previous findings that fenofibrate increases secretion of kallistatin by ~300% in aortic VSMC in vitro and reduces aortic OPN concentration by ~95% in a mouse model of AAA.…”

Section: Study Population and Power Calculationmentioning

confidence: 99%

“…[21][22][23] Obesity and visceral fat accumulation are risk factors for AAA, with analysis suggesting circulating adipokines, in particular resistin, may be the cause. 24 Previous studies have reported that fenofibrate downregulates resistin production from visceral adipose tissue, thus providing a further potential mechanism by which fenofibrate could stabilise AAAs. 25,26 A large body of data implicates MMPs in AAA.…”

Section: Introductionmentioning

confidence: 99%

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Fenofibrate in the management of AbdoMinal aortic aneurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

Rowbotham

Bourke

et al. 2016

Int J Clin Trials

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INTRODUCTIONAn abdominal aortic aneurysm (AAA) is a permanent dilatation of the infrarenal aorta that can lead to death as a result of aortic rupture.1,2 AAAs are present in ~5% of men and ~1% of women aged over 65 years, but have no known medical therapy. [3][4][5][6][7] Current guidelines comprise regular ultrasound imaging until a diameter threshold is reached (typically 55 mm), at which point surgical intervention is considered. 8 Patients with symptomatic or rapidly expanding AAAs (>10 mm/year) should also be ABSTRACT Background: Abdominal aortic aneurysms (AAAs) are a leading cause of mortality worldwide but have no recognised medical therapy. Pre-clinical studies indicate that osteopontin plays an important role in the pathogenesis of AAA via a number of mechanisms. This trial aims to assess the potential of fenofibrate to favourably alter biomarkers associated with AAA pathology. Methods: Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME)-2 is a multi-centre, prospective, randomised, double-blind, placebo-controlled clinical trial to assess the effect of 24 weeks of oral therapy with 145 mg of fenofibrate on key pathological markers of AAA. A total of 140 participants with an AAA measuring between 35-49 mm will be randomly assigned to either 145 mg of fenofibrate once per day or identical placebo for a period of 24 weeks. Primary outcome measures will be serum concentrations of osteopontin and kallistatin. Secondary outcome measures will include serum levels of resistin, lipids, matrix metalloproteinases and pro-inflammatory cytokines, circulating concentrations of AAA biomarkers, and AAA diameter as assessed by ultrasound. Conclusions: This study represents the next step in the assessment of a potential novel medical therapy for AAA.

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Section: Study Population and Power Calculationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fenofibrate in the management of AbdoMinal aortic aneurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

Rowbotham

Bourke

et al. 2016

Int J Clin Trials

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“…Controls had maximum infrarenal aortic diameter ≤ 25mm. The definitions of risk factors such as hypertension, dyslipidemia, diabetes, coronary heart disease (CHD) and smoking were as previously described [21].…”

Section: Patientsmentioning

confidence: 99%

A single nucleotide polymorphism in exon 3 of the kallikrein 1 gene is associated with large but not small abdominal aortic aneurysm

et al. 2011

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Objective: Abdominal aortic aneurysm (AAA) is a late onset degenerative condition with an inherited component thought to be due to multiple risk alleles. A locus on chromosomes 19q13 has been previously associated with AAA. The gene encoding kallikrein 1 (KLK1) is located on chromosome 19q13 and the single nucleotide polymorphism (SNP) rs5516 has been previously shown to lead to structural changes in the KLK1 transcription regulatory region. The aim of this study was to investigate whether rs5516 was associated with AAA and aortic diameter. Methods:We performed a case-control study on two independent subject groups from Western Australia (n=1304) and Queensland (n=325) of which 609 and 225 had an AAA, respectively. In addition we analysed RNA extracted from abdominal aortic biopsies from 12 patients undergoing AAA surgery and 6 organ donors.Results: After adjusting for other risk factors the G allele of the rs5516 polymorphism was associated with large but not small AAA using a dominant model in the Western Australian men and a recessive model in Queensland subjects. In subjects with large AAA the G allele was associated with aortic diameter. The short splice variant of KLK1 was upregulated within AAA compared to control biopsies. Conclusion:This study suggests that a genetic polymorphism in KLK1 may contribute to the risk of developing later stage AAA.

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“…7,8 For the current study, genotyping was undertaken in all men with AAAs from whom DNA was available (n¼640) and 1071 randomly selected age-matched men without an AAA were taken as controls. Any SNPs found to be significantly associated with aortic diameter were further assessed in an independent cohort of subjects from New Zealand.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

“…9 The definitions of clinical risk factors such as hypertension, dyslipidemia, diabetes, coronary heart disease and waist-to-hip ratio were as previously described. 7 …”

Section: Study Design and Subjectsmentioning

confidence: 99%

A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm

et al. 2010

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Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5a reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C4T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P¼0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs. Keywords: aorta; aneurysm; sex hormones INTRODUCTION Abdominal aortic aneurysm (AAA) primarily affects men, with population-screening studies demonstrating an increased prevalence of approximately fivefold compared with women. 1 Currently, the reasons for the male propensity for AAA are not known, but maybe linked to sex hormones, as in experimental models androgens have been positively linked to aortic dilatation. 2 The production, metabolism and response to sex hormones are controlled by an array of enzymes and receptors, including steroid 5a reductase, aromatase (estrogen synthetase), androgen and estrogen receptors. 3,4 Steroid 5a reductase enzymes are responsible for the conversion of testosterone to the more potent androgen dihydrotestosterone. 3 Aromatase (estrogen synthetase) is a cytochrome P450 enzyme that converts androgen precursor steroids to estrogens. 4 The responses to circulating sex hormones are determined by the androgen and estrogen receptors. Genetic factors appear to have an important role in the production, metabolism and response to male sex hormones, and therefore maybe relevant to AAA, which has been shown to have inherited risk factors. 5,6 We selected four genes important in the production, metabolism and response to sex hormones to examine the association of genetic polymorphisms with aortic dilatation. We hypothesized that single-nucleotide polymorphisms (SNPs) in the steroid 5a reductase,

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Obesity, Adipokines, and Abdominal Aortic Aneurysm

Cited by 145 publications

References 28 publications

Fenofibrate in the management of AbdoMinal aortic aneurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

Fenofibrate in the management of AbdoMinal aortic aneurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

A single nucleotide polymorphism in exon 3 of the kallikrein 1 gene is associated with large but not small abdominal aortic aneurysm

A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm

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