Background A modest (41%) reduction in abdominal aortic aneurysm (AAA) growth rate is likely to delay AAA-related events (surgery or rupture) by 5 years, making the notion of AAA medical treatment ...very appealing. Randomized controlled trials of commonly used existing medications are expensive and ethically questionable. This study reviewed the independent associations of commonly used medications and AAA growth during a 25-year period of AAA surveillance. Methods The study included all patients monitored through an AAA screening and surveillance program. Records of AAA size, risk factors, outcomes, death, and medications were entered into a continually updated database. AAA growth rates were calculated using a flexible hierarchical model. A multivariate model was used to test for associations independent of confounders. Results The study comprised 1269 patients (94.1% men) who had a mean age of 67 years. The median starting diameter was 35 mm, the end diameter was 44 mm, and follow-up was 3.4 years. Drugs used in the treatment of diabetes were associated with a 56% reduction in AAA growth rate ( P = .01) independent of confounding factors, including other therapeutic agents ( P = .003). Angiotensin-receptor blockers and potassium-sparing diuretics were also associated with slower AAA growth rates, although these effects were not independent of all confounders. Conclusion Diabetes or its medications, or both, have a negative effect on AAA growth. Because of polypharmacy, demonstrating the independent effects of individual drugs affecting the renin-angiotensin system was not possible. In light of this analysis, however, strong associations between angiotensin-receptor blockers and aldosterone-receptor blockers and slowed AAA progression are credible.
Summary Background Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to ...identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. Methods In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. Findings We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0·90 SD 0·23) was strongly associated with LDL-C concentration (p=1·4 × 10−77 ; R2 =0·11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1·0 SD 0·21) than did WHII controls (p=4·5 × 10−16 ), as did the mutation-negative Belgian patients (0·99 0·19; p=5·2 × 10−20 ). The score was also higher in UK (0·95 0·20; p=1·6 × 10−5 ) and Belgian (0·92 0·20; p=0·04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. Interpretation In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. Funding British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.
Abstract Background Despite excessive rates of cardiovascular risk factors such as hypertension, diabetes and obesity, Afro-Caribbeans have lower mortality rates from coronary heart disease (CHD) ...compared to Caucasians. This study evaluated the association of genetic risk markers previously identified in Caucasians, with CHD in Afro-Caribbeans. Methods We studied 537 Afro-Caribbeans subjects (178 CHD-cases and 359 controls) who were genotyped for 19 CHD-related SNPs. A genetic risk score (GRS) incorporating the 19 SNPs was calculated. These participants were compared to 1360 Caucasian subjects from the-second Northwick Park Heart Study. Results In Afro-Caribbeans, patients with CHD had higher rates of hypertension (78.7% vs 30.1%), hypercholesterolemia (52.8% vs 15.0%), diabetes (53.9% vs 14.8%), and were more often male (64.0% vs 43.7%) and smokers (27.5% vs 13.4%) compared to non-CHD controls (all p<0.001). The GRS was higher in Afro-Caribbeans with CHD compared to those without CHD (13.90 vs 13.17; p<0.001) and was significantly associated with CHD after adjustment for cardiovascular risk factors with an odds ratio of 1.40 (95% CI 1.09-1.80) per standard deviation change. There were significant differences in allelic distributions between the two ethnic groups, for 14 of the 19 SNPs. The GRS was substantially lower in Afro-Caribbean controls compared to Caucasian controls: 13.17 vs 16.59; p<0.001. Conclusion This study demonstrates that a multilocus-GRS composed of 19 SNPs associated with CHD in Caucasians is a strong predictor of the disease in Afro-Caribbeans. The differences in CHD occurrence between Afro-Caribbeans and Caucasians might be a result of significant discrepancies in common gene variant distribution.
Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine ...by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS.
In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13.
IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 μg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 95% CI 0·03-0·72; p=0·01).
FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.
Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is ...still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.
We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.
In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate.
Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.
UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.
Secretory Phospholipase A2 -IIA and Cardiovascular Disease Holmes, Michael V., MSc; Simon, Tabassome, MD, PhD; Exeter, Holly J., PhD ...
Journal of the American College of Cardiology,
11/2013, Letnik:
62, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2 )-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2 -IIA mass or sPLA2 enzyme ...activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events MVE in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2 -IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2 -IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval CI: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2 -IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA2 -IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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