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1.
Artigo em Inglês | MEDLINE | ID: mdl-33741209

RESUMO

OBJECTIVE: To encompass the needs of all stakeholders and allow effective data synthesis from trials, registries, and other studies; a core outcome set for infrarenal abdominal aortic aneurysm (AAA) repair is needed. In this first stage, the aim was to report the range, frequency, and time of pre-specified outcomes reported following AAA repair. DATA SOURCES: Medline, Embase, and CENTRAL databases 2010 - 2019 were searched using ProQuest Dialog™. REVIEW METHODS: The systematic review was reported to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA), PROSPERO registration CRD42019130119. Outcomes were coded using Core Outcome Measures in Effectiveness Trials (COMET) taxonomy and presented separately for intact and rupture repairs, endovascular aneurysm repair (EVAR) and open repair, and time from repair (acute < 90 days vs. ≥ 1 year) (COMET Initiative 1582). RESULTS: For intact AAA and rupture repair, a total of 231 and 70 reports with 589 255 and 177 465 patients respectively were included: only 98 and 19 respectively provided ≥ 1 year outcomes. Most studies were retrospective, with 13 randomised trials of intact AAA repair and five randomised trials of ruptured AAA repair. For intact AAA, the most common pre-specified COMET taxonomy outcomes were mortality (181), vascular complications (137), and re-intervention (52). EVAR studies dominated the vascular outcomes in acute and later time periods: excluding 47 reports from device registries, reduced vascular outcomes to 83. For ruptured AAA, the three most common outcomes were mortality (64), vascular (11), and hospital stay (10). The range of outcomes reported was wide with functioning outcomes reported from most randomised trials but few retrospective studies. CONCLUSION: This review identifies the paucity of long term data and the disproportionate attention paid to vascular complications vs. patient functioning outcomes, this skew being accentuated by reporting from EVAR device registries. These data will inform focus groups, prior to a pan-European Delphi consensus, involving clinicians, patients, carers and providers, for developing core outcomes for repair of intact and ruptured AAA.

2.
Value Health ; 24(3): 369-376, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33641771

RESUMO

OBJECTIVES: To investigate the safety and cost-effectiveness of lengthening the time between surveillance ultrasound scans in the UK Abdominal Aortic Aneurysm (AAA) Screening Programme. METHODS: A discrete event simulation model was used to evaluate the cost-effectiveness of AAA screening for men aged 65, comparing current surveillance intervals to 6 alternative surveillance interval strategies that lengthened the time between surveillance scans for 1 or more AAA size categories. The model considered clinical events and costs incurred over a 30-year time horizon and the cost per quality-adjusted life year (QALY). The model adopted the National Health Service perspective and discounted future costs and benefits at 3.5%. RESULTS: Compared with current practice, alternative surveillance strategies resulted in up to a 4% reduction in the number of elective AAA repairs but with an increase of up to 1.6% in the number of AAA ruptures and AAA-related deaths. Alternative strategies resulted in a small reduction in QALYs compared to current practice but with reduced costs. Two strategies that lengthened surveillance intervals in only very small AAAs (3.0-3.9 cm) provided, at a cost-effectiveness threshold of £20 000 per QALY, the highest positive incremental net benefit. There was negligible chance that current practice is the most cost-effective strategy at any threshold below £40 000 per QALY. CONCLUSIONS: Lengthening surveillance intervals in the UK Abdominal Aortic Aneurysm Screening Programme, especially for small AAA, can marginally reduce the incremental cost per QALY of the program. Nevertheless, whether the cost savings from refining surveillance strategies justifies a change in clinical practice is unclear.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Programas de Rastreamento/economia , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Feminino , Humanos , Masculino , Modelos Econômicos , Método de Monte Carlo , Medicina Estatal , Fatores de Tempo , Ultrassonografia , Reino Unido
4.
Nat Genet ; 52(12): 1303-1313, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33199917

RESUMO

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

5.
Circulation ; 142(17): 1633-1646, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-32981348

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. METHODS: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. RESULTS: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. CONCLUSIONS: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32912760

RESUMO

OBJECTIVE: Left renal vein (LRV) ligation is performed during open abdominal aortic aneurysm (AAA) repair to facilitate proximal anastomosis. Its impact on short, medium, and long term renal function has not been investigated in detail using appropriately validated endpoints. METHODS: This was a nested case control study using data from a prospectively maintained AAA institutional dataset (tertiary centre). A total of 76 patients who underwent elective open AAA repair and had LRV ligation (1 January 2012 to 1 January 2018) were individually case matched based on age (within two years), sex, estimated glomerular filtration rate (eGFR), American Society of Anesthesiologist (ASA) score, chronic kidney disease (CKD) stage, and history of diabetes with 76 patients who had open AAA repair without LRV ligation. Renal outcomes were compared between groups, including proportion of patients developing acute kidney injury (AKI) using the Kidney Disease Improving Global Outcomes (KDIGO) criteria, proportion developing major adverse kidney events (MAKE90) at 90 days (comprising mortality and/or decrease in eGFR >25%), and absolute decrease in eGFR at latest follow up. RESULTS: A higher proportion of patients developed AKI and MAKE90 in the LRV ligation group (AKI: 11 patients [14.8%] vs. 2 [2.6%], p = .009; MAKE90: 6 [7.9%] vs. 1 [1.3%] p = .053, in the LRV ligation and the non-LRV ligation groups, respectively) - even though the difference in the MAKE90 endpoint was not statistically significant. Changes in eGFR were not statistically different in the LRV ligation group at 90 days (4.0 ± 1.1 mL/min/1.73 m2vs. 4.4 ± 2.1, p = .64) or by the time of latest follow up (median: 28 months; 3.7 ± 1.6 vs. 2.6 ± 2.0, p = .55). CONCLUSION: Ligation of the LRV is associated with increased levels of AKI and renal deterioration in the early post-operative phase using validated reporting criteria; however, long term renal function does not seem to be affected.

7.
Circ Genom Precis Med ; 13(5): 417-423, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862661

RESUMO

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8-as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8. RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; P=1.1×10-6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

8.
Eur J Vasc Endovasc Surg ; 60(5): 703-710, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32718828

RESUMO

OBJECTIVE: Opportunities for timely recognition of chronic limb-threatening ischaemia (CLTI) within primary care, such as performing cardiovascular assessment during clinical consultation, are possibly being missed. This study aimed to investigate for potential "missed opportunities" within primary care. METHODS: This was a population based cohort study, using the UK's Clinical Practice Research Datalink (CPRD). Patients undergoing a major amputation for CLTI between 1 January 2000 and 31 December 2016 were included. Primary care consultation and patient clinical data within the one year period prior to amputation were extracted from the CPRD. Dates of last primary care consultation and cardiovascular assessment prior to amputation were evaluated. Timings of latest cardiovascular assessments were stratified into "recent" (7-90 days before amputation) and "late" (> 91 days). RESULTS: In total, 3 260 patients were included. In the year prior to amputation, patients attended a median of 19 (range 9-32) primary care consultations; however, prescription of secondary preventive medications was poor (antiplatelet 49.7%; lipid lowering agent 40.7%). Overall, 2 175 patients (66.7%) attended a primary care consultation 7-30 days before their amputation. However, only 416 (12.8%) underwent a cardiovascular assessment within this period, with 2 073 (63.6%) undergoing no assessment within 90 days of their amputation. Of these 2 073 patients, 1 230 (59.3%) had a primary care consultation 7-30 days before their procedure. Patients undergoing "late" assessment were younger (p = .003), with higher systolic (p = .008) and diastolic (p = .001) blood pressures than those undergoing "recent" assessment. Differences were also observed between assessment timings by deprivation (p = .003) and ethnicity (p = .006). CONCLUSION: Missed opportunities for timely recognition potentially exist and may be related to age, deprivation, and ethnicity. Further work is required to investigate these factors, as well as individual amputations to identify the causes precipitating amputation. Greater emphasis on the medical management of peripheral arterial disease and identifying cardiovascular risk factors in patients who may not fit the "at risk" stereotype, are also required.


Assuntos
Amputação/estatística & dados numéricos , Isquemia/diagnóstico , Diagnóstico Ausente/estatística & dados numéricos , Doença Arterial Periférica/diagnóstico , Atenção Primária à Saúde/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença Crônica/terapia , Diagnóstico Precoce , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Isquemia/prevenção & controle , Isquemia/cirurgia , Extremidade Inferior/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Diagnóstico Ausente/prevenção & controle , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/cirurgia , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Fatores Socioeconômicos , Reino Unido
9.
PLoS Genet ; 16(4): e1008629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282858

RESUMO

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Oxirredutases/genética , Alelos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Conjuntos de Dados como Assunto , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Feminino , Homozigoto , Humanos , Fígado/enzimologia , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/enzimologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade
10.
J Vasc Surg ; 71(2): 669-681.e2, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31676182

RESUMO

OBJECTIVE: Patients presenting with chronic limb-threatening ischemia and diabetic foot ulceration (DFU) are at high risk of major lower limb amputation. Long-standing concern exists regarding late presentation and delayed management contributing to increased amputation rates. Despite multiple guidelines existing on the management of both conditions, there is currently no accepted time frame in which to enact specialist care and treatment. This systematic review aimed to investigate potential time delays in the identification, referral, and management of both chronic limb-threatening ischemia and DFU. METHODS: A systematic review conforming to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards was performed searching MEDLINE, Embase, The Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature from inception to November 14, 2018. All English-language qualitative and quantitative articles investigating or reporting the identification, causes, and outcomes of time delays within "high-income" countries (annual gross domestic product per person >$15,000) were included. Data were extracted independently by the investigators. Given the clinical crossover, both conditions were investigated together. A study protocol was designed and registered at the International Prospective Register of Systematic Reviews. RESULTS: A total of 4780 articles were screened, of which 32 articles, involving 71,310 patients and 1388 health care professionals, were included. Twenty-three articles focused predominantly on DFU. Considerable heterogeneity was noted, and only 12 articles were deemed of high quality. Only four articles defined a delay, but this was not consistent between studies. Median times from symptom onset to specialist health care assessment ranged from 15 to 126 days, with subsequent median times from assessment to treatment ranging from 1 to 91 days. A number of patient and health care factors were consistently reported as potentially causative, including poor symptom recognition by the patient, inaccurate health care assessment, and difficulties in accessing specialist services. Twenty articles reported outcomes of delays, namely, rates of major amputation, ulcer healing, and all-cause mortality. Although results were heterogeneous, they allude to delays being associated with detrimental outcomes for patients. CONCLUSIONS: Time delays exist in all aspects of the management pathway, which are in some cases considerable in length. The causes of these are complex but reflect poor patient health-seeking behaviors, inaccurate health care assessment, and barriers to referral and treatment within the care pathway. The adoption of standardized limits for referral and treatment times, exploration of missed opportunities for diagnosis, and investigation of novel strategies for providing specialist care are required to help reduce delays.


Assuntos
Pé Diabético/diagnóstico , Pé Diabético/terapia , Isquemia/diagnóstico , Isquemia/terapia , Extremidade Inferior/irrigação sanguínea , Doença Crônica , Diagnóstico Tardio , Humanos , Tempo para o Tratamento , Resultado do Tratamento
11.
Eur J Vasc Endovasc Surg ; 59(1): 92-97, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680049

RESUMO

OBJECTIVE: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study. METHODS: ARIC identified 408 clinically diagnosed AAAs among 8 962 individuals of European ancestry during a median of 22 years of follow up. The Greek case control study included 341 AAAs of European ancestry recruited in a tertiary referral centre and 292 geographically and ethnically matched controls recruited from the same institution. A Cox proportional hazards model was used to analyse the ARIC data and logistic regression to analyse the Greek data. RESULTS: In ARIC, rs9316871 and rs3827066 were significantly associated with AAA risk (HR [p] was 0.77 [.004] and 1.22 [.03], respectively), rs2836411 was associated at borderline significance (1.13 [.08]), whereas rs1795061 was not associated (p = .55). In the Greek case control study, rs1795061 and rs2836411 were significantly associated with AAA (OR [p] was 1.66 [< .001] and 1.29 [.04], respectively), whereas rs9316871 was not (p = .81). Genotyping of rs3827066 did not succeed. In the meta-analysis of the two studies, the association for rs9316871and rs2836411 was statistically significant and consistent between the two studies: p = .02 and .007, respectively. CONCLUSIONS: Associations between rs9316871and rs2836411 and AAA risk were replicated in the meta-analysis of the two independent cohorts, providing further support for the importance of these loci in the aetiology of AAA.


Assuntos
Aneurisma da Aorta Abdominal/genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Aneurisma da Aorta Abdominal/epidemiologia , Proteínas de Ligação a DNA/genética , Grécia/epidemiologia , Histona-Lisina N-Metiltransferase/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores de Transcrição/genética , Regulador Transcricional ERG/genética , Estados Unidos/epidemiologia
12.
Eur J Vasc Endovasc Surg ; 59(6): 899-909, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31870694

RESUMO

OBJECTIVES: The incidence of acute kidney injury (AKI) after open (OAR) or endovascular (EVAR) aortic repair is unknown. This research assessed the proportion of patients who develop AKI after aortic intervention using validated criteria, and explored AKI risk factors. METHODS: This was a multicentre national prospective cohort study. Eleven centres recruited patients undergoing EVAR or OAR (September 2017-December 2018). Serum creatinine (SCr) and urine outputs were measured over a minimum of 48 h or throughout the index inpatient stay to define post-operative AKI using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Renal decline at 30 days was calculated using estimated glomerular filtration rate (eGFR) and the Major Adverse Kidney Events (MAKE) 30 day composite endpoint (consisting of: death, new dialysis, > 25% eGFR decline). RESULTS: 300 patients (mean age: 71 years, standard deviation [SD] 4 years; 9% females) were included, who underwent: infrarenal endovascular aneurysm repair (EVAR) 139 patients, fenestrated EVAR (fEVAR) 30, branched EVAR (bEVAR) seven, infrarenal open aneurysm repair (OAR) 98, juxtarenal OAR 26. Overall, 24% of patients developed stage 1 AKI (defined at 48 h as per KDIGO), 2.7% stage 2 AKI and 1% needed renal replacement therapy before discharge. AKI proportions per intervention were: infrarenal EVAR 18%; fEVAR 27%; bEVAR 71%; infrarenal OAR 41%; juxtarenal OAR 63%. Older age (odds ratio [OR] 1.44 for EVAR, 1.58 for OAR), lower baseline eGFR (OR 0.88 EVAR, 0.74 OAR), and ischaemic heart disease (OR 4.42 EVAR, 5.80 OAR) were the main predictors of AKI for infrarenal EVAR and OAR. Overall, 24% developed the MAKE30 endpoint. All patients who died (0.6%) or developed a major cardiac event (5.6%) at one year had developed AKI. CONCLUSION: AKI and short term renal decline after aortic intervention are common. Age, renal function, and cardiovascular disease are the main risk factors. Research should now focus on AKI prevention in this high risk group.


Assuntos
Lesão Renal Aguda/epidemiologia , Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/fisiopatologia , Fatores Etários , Idoso , Creatinina , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Incidência , Rim/fisiopatologia , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Estudos Prospectivos , Medição de Risco , Fatores de Risco
13.
J Am Heart Assoc ; 8(20): e013743, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31595818

RESUMO

Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the breakdown of elastin within the aortic tunica media, leading to aortic dilatation and rupture. The aim of this study was to investigate the association of plasma desmosine (pDES), an elastin-specific degradation product, with disease severity and clinical outcome in patients with AAA. Methods and Results We measured pDES and serum biomarker concentrations in 507 patients with AAAs (94% men; mean age, 72.4±6.1 years; mean AAA diameter, 48±8 mm) and 162 control subjects (100% men; mean age, 71.5±4.4 years) from 2 observational cohort studies. In the longitudinal cohort study (n=239), we explored the incremental prognostic value of pDES on AAA events. pDES was higher in patients with AAA compared with control subjects (mean±SD: 0.46±0.22 versus 0.33±0.16 ng/mL; P<0.001) and had the strongest correlation with AAA diameter (r=0.39; P<0.0001) of any serum biomarker. After adjustment for baseline AAA diameter, pDES was associated with an AAA event (hazard ratio, 2.03 per SD increase [95% CI, 1.02-4.02]; P=0.044). In addition to AAA diameter, pDES provided incremental improvement in risk stratification (continuous net reclassification improvement, 34.4% [95% CI, -10.8% to 57.5%; P=0.09]; integrated discrimination improvement, 0.04 [95% CI, 0.00-0.15; P=0.050]). Conclusions pDES concentrations predict disease severity and clinical outcomes in patients with AAA. Clinical Trial Registration http://www.isrctn.com. Unique identifier: ISRCTN76413758.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/sangue , Desmosina/sangue , Idoso , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/epidemiologia , Biomarcadores/sangue , Cateterismo Cardíaco , Feminino , Seguimentos , Humanos , Incidência , Masculino , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Ultrassonografia , Reino Unido/epidemiologia
14.
BMJ Open ; 9(9): e031257, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481569

RESUMO

INTRODUCTION: Severe limb ischaemia (SLI) is the end stage of peripheral arterial occlusive disease where the viability of the limb is threatened. Around 25% of patients with SLI will ultimately require a major lower limb amputation, which has a substantial adverse impact on quality of life. A newly established rapid-access vascular limb salvage clinic and modern revascularisation techniques may reduce amputation rate. The aim of this study was to investigate the 12-month amputation rate in a contemporary cohort of patients and compare this to a historical cohort. Secondary aims are to investigate the use of frailty and cognitive assessments, and cardiac MRI in risk-stratifying patients with SLI undergoing intervention and establish a biobank for future biomarker analyses. METHODS AND ANALYSIS: This single-centre prospective cohort study will recruit patients aged 18-110 years presenting with SLI. Those undergoing intervention will be eligible to undergo additional venepuncture (for biomarker analysis) and/or cardiac MRI. Those aged ≥65 years and undergoing intervention will also be eligible to undergo additional frailty and cognitive assessments. Follow-up will be at 12 and 24 months and subsequently via data linkage with NHS Digital to 10 years postrecruitment. Those undergoing cardiac MRI and/or frailty assessments will receive additional follow-up during the first 12 months to investigate for perioperative myocardial infarction and frailty-related outcomes, respectively. A sample size of 420 patients will be required to detect a 10% reduction in amputation rate in comparison to a similar sized historical cohort, with 90% power and 5% type I error rate. Statistical analysis of this comparison will be by adjusted and unadjusted logistic regression analyses. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the UK National Research Ethics Service (19/LO/0132). Results will be disseminated to participants via scientific meetings, peer-reviewed medical journals and social media. TRIAL REGISTRATION NUMBER: NCT04027244.


Assuntos
Amputação/métodos , Isquemia/cirurgia , Salvamento de Membro/métodos , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/complicações , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Isquemia/etiologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/cirurgia , Estudos Prospectivos , Fatores de Tempo , Adulto Jovem
15.
Eur J Vasc Endovasc Surg ; 58(3): 328-333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327538

RESUMO

INTRODUCTION: Over the short term endovascular aneurysm repair (EVAR) is associated with superior outcomes compared with open repair; however, the progression of renal function after EVAR remains unknown because of the use of inconsistent reporting measures. The aim was to define long term renal decline following elective EVAR using estimated glomerular filtration rate (eGFR). METHODS: The prospectively maintained in house database was used to identify consecutive patients having elective EVAR who had been followed up for more than five years. Overall, 275 patients (23 females, 8%; mean age, 75 years) who were not previously on renal replacement therapy (RRT) were included (January 2000 to July 2010). Pre-operative, post-operative, and most recent eGFR values were evaluated using the chronic kidney disease epidemiology collaboration equation. The primary outcome was change in eGFR at latest follow up. RESULTS: Patients were followed up over a median of 9 years (range 5-17 years). Their mean eGFR dropped from a pre-operative value of 67 mL/min/1.73 m2 (standard deviation [SD]: 9.4) to 52 mL/min/1.73 m2 (SD 7.7), which amounts to a yearly loss of 1.7 units; six patients (2%) required RRT (dialysis) during late follow up. Patients requiring RRT and those with an eGFR loss exceeding 20% at latest follow up compared with baseline were more likely to die during late follow up (odds ratio 2.4 and 3.3 respectively, p < .001). CONCLUSION: This analysis, with some of the longest available follow up to date, suggests that patients undergoing EVAR may experience a significant long term decrease in renal function. This needs to be taken into account when offering EVAR in younger patients; renal follow up and preservation should be optimised in this patient group.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares/efeitos adversos , Previsões , Taxa de Filtração Glomerular/fisiologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Reino Unido/epidemiologia
16.
Circ Genom Precis Med ; 12(2): e002413, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30657332

RESUMO

BACKGROUND: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. METHODS: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. RESULTS: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05). CONCLUSIONS: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Receptores de Interleucina-6/metabolismo , Alelos , Angiotensina II/toxicidade , Animais , Anticorpos/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/mortalidade , Biomarcadores/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-6/sangue , Modelos Lineares , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Transdução de Sinais , Taxa de Sobrevida , Fator de Crescimento Transformador beta/imunologia
18.
Diabetes ; 68(1): 226-234, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389748

RESUMO

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic ß-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.


Assuntos
Receptores de Ativinas Tipo I/genética , Diabetes Mellitus Tipo 2/genética , Análise de Sequência de DNA/métodos , Algoritmos , Exoma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos
19.
Health Technol Assess ; 22(43): 1-142, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30132754

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) screening programmes have been established for men in the UK to reduce deaths from AAA rupture. Whether or not screening should be extended to women is uncertain. OBJECTIVE: To evaluate the cost-effectiveness of population screening for AAAs in women and compare a range of screening options. DESIGN: A discrete event simulation (DES) model was developed to provide a clinically realistic model of screening, surveillance, and elective and emergency AAA repair operations. Input parameters specifically for women were employed. The model was run for 10 million women, with parameter uncertainty addressed by probabilistic and deterministic sensitivity analyses. SETTING: Population screening in the UK. PARTICIPANTS: Women aged ≥ 65 years, followed up to the age of 95 years. INTERVENTIONS: Invitation to ultrasound screening, followed by surveillance for small AAAs and elective surgical repair for large AAAs. MAIN OUTCOME MEASURES: Number of operations undertaken, AAA-related mortality, quality-adjusted life-years (QALYs), NHS costs and cost-effectiveness with annual discounting. DATA SOURCES: AAA surveillance data, National Vascular Registry, Hospital Episode Statistics, trials of elective and emergency AAA surgery, and the NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP). REVIEW METHODS: Systematic reviews of AAA prevalence and, for elective operations, suitability for endovascular aneurysm repair, non-intervention rates, operative mortality and literature reviews for other parameters. RESULTS: The prevalence of AAAs (aortic diameter of ≥ 3.0 cm) was estimated as 0.43% in women aged 65 years and 1.15% at age 75 years. The corresponding attendance rates following invitation to screening were estimated as 73% and 62%, respectively. The base-case model adopted the same age at screening (65 years), definition of an AAA (diameter of ≥ 3.0 cm), surveillance intervals (1 year for AAAs with diameter of 3.0-4.4 cm, 3 months for AAAs with diameter of 4.5-5.4 cm) and AAA diameter for consideration of surgery (5.5 cm) as in NAAASP for men. Per woman invited to screening, the estimated gain in QALYs was 0.00110, and the incremental cost was £33.99. This gave an incremental cost-effectiveness ratio (ICER) of £31,000 per QALY gained. The corresponding incremental net monetary benefit at a threshold of £20,000 per QALY gained was -£12.03 (95% uncertainty interval -£27.88 to £22.12). Almost no sensitivity analyses brought the ICER below £20,000 per QALY gained; an exception was doubling the AAA prevalence to 0.86%, which resulted in an ICER of £13,000. Alternative screening options (increasing the screening age to 70 years, lowering the threshold for considering surgery to diameters of 5.0 cm or 4.5 cm, lowering the diameter defining an AAA in women to 2.5 cm and lengthening the surveillance intervals for the smallest AAAs) did not bring the ICER below £20,000 per QALY gained when considered either singly or in combination. LIMITATIONS: The model for women was not directly validated against empirical data. Some parameters were poorly estimated, potentially lacking relevance or unavailable for women. CONCLUSION: The accepted criteria for a population-based AAA screening programme in women are not currently met. FUTURE WORK: A large-scale study is needed of the exact aortic size distribution for women screened at relevant ages. The DES model can be adapted to evaluate screening options in men. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020444 and CRD42016043227. FUNDING: The National Institute for Health Research Health Technology Assessment programme.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Programas de Rastreamento/economia , Ultrassonografia/economia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Simulação por Computador , Análise Custo-Benefício , Feminino , Humanos , Prevalência , Anos de Vida Ajustados por Qualidade de Vida , Reino Unido
20.
Lancet ; 392(10146): 487-495, 2018 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-30057105

RESUMO

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Programas de Rastreamento/economia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/economia , Aneurisma da Aorta Abdominal/mortalidade , Análise Custo-Benefício , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Anos de Vida Ajustados por Qualidade de Vida
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