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1.
BMJ Open ; 10(11): e043634, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154065

RESUMO

OBJECTIVE: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. SUMMARY OF KEY POINTS: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. CONCLUSION: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.

3.
Heart ; 106(22): 1726-1731, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32826289

RESUMO

OBJECTIVE: To study the association of cardiac rehabilitation and physical activity with temporal changes in health-related quality of life (HRQoL) following acute myocardial infarction (AMI). METHODS: Evaluation of the Methods and Management of Acute Coronary Events-3 is a nationwide longitudinal prospective cohort study of 4570 patients admitted with an AMI between 1 November 2011 and 17 September 2013. HRQoL was estimated using EuroQol 5-Dimension-3 Level Questionnaire at hospitalisation, 30 days, and 6 and 12 months following hospital discharge. The association of cardiac rehabilitation and self-reported physical activity on temporal changes in HRQoL was quantified using inverse probability of treatment weighting propensity score and multilevel regression analyses. RESULTS: Cardiac rehabilitation attendees had higher HRQoL scores than non-attendees at 30 days (mean EuroQol 5-Visual Analogue Scale (EQ-VAS) scores: 71.0 (SD 16.8) vs 68.6 (SD 19.8)), 6 months (76.0 (SD 16.4) vs 70.2 (SD 19.0)) and 12 months (76.9 (SD 16.8) vs 70.4 (SD 20.4)). Attendees who were physically active ≥150 min/week had higher HRQoL scores compared with those who only attended cardiac rehabilitation at 30 days (mean EQ-VAS scores: 79.3 (SD 14.6) vs 70.2 (SD 17.0)), 6 months (82.2 (SD 13.9) vs 74.9 (SD 16.7)) and 12 months (84.1 (SD 12.1) vs 75.6 (SD 17.0)). Cardiac rehabilitation and self-reported physical activity of ≥150 min/week were each positively associated with temporal improvements in HRQoL (coefficient: 2.12 (95% CI 0.68 to 3.55) and 4.75 (95% CI 3.16 to 6.34), respectively). CONCLUSIONS: Cardiac rehabilitation was independently associated with temporal improvements in HRQoL at up to 12 months following hospitalisation, with such changes further improved in patients who were physically active.

4.
Trials ; 21(1): 694, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738919

RESUMO

BACKGROUND: Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. METHODS: The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. RESULTS: 'Under-served groups' was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. CONCLUSIONS: The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations.

5.
BMC Cardiovasc Disord ; 20(1): 46, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013880

RESUMO

BACKGROUND: The 'My Experience of Taking Medicines' (MYMEDS) questionnaire is a self-reporting tool for identifying modifiable adherence barriers among individuals prescribed post-myocardial infarction (MI) secondary prevention medicines (SPM) in clinical practice. It was found to be a useful tool to support the conduction of patient-centred consultation in cardiology outpatient leading to improved outcomes including better adherence to SPM and patient satisfaction. This study describes the rationale and development of the MYMEDS tool, its performance and usefulness in identifying modifiable barriers to adherence in cardiology medical practice including user feedback of 204 consecutive post-MI patients who completed an evaluation based on MYMEDS. METHODS: Modifiable non-adherence factors were initially identified based on literature review and stakeholder feedback. A draft MYMEDS questionnaire was piloted in 10 patients and adapted accordingly. The final version comprises six sections, covering current medicines, understanding and satisfaction with medicines, concerns about medicines, practical adherence barriers, fitting medicines into daily routine, and adherence to individual SPMs. The questionnaire was mailed to post-MI patients who then attended an outpatient medicines optimisation clinic. RESULTS: Mean age was 70.5 years and 67.6% were male. The tool was effective in revealing modifiable adherence barriers that could be addressed during the consultation. There were high rates of concern that SPMs could be harmful (33.2%) or overprescribed (43.2%), practical issues with swallowing medicines (8.2%), opening packaging (7.3%) or accessing repeat prescriptions (5.2%), forgetfulness (19.7%), and concerns about inconvenience (13.5%). Mean number of barriers per patient was 1.8 ± 1.5. The medications most commonly associated with non-adherence were statins (21.5%), angiotensin II receptor blockers (21.1%), and antiplatelet agents (18.5%). In total, 42.5% of patients acknowledged non-adherence behaviour. Patient feedback on MYMEDS was positive, with near-unanimous agreement that it was simple, clear and not too long, and that it enabled them to raise any concerns they had about their medicines. Patients reported that their individual medicines related needs were better addressed. CONCLUSIONS: MYMEDS is a practical tool that can successfully identify modifiable barriers to SPM adherence which can be addressed in a clinical setting. It can be easily rolled out in daily clinical practice to enable individualised person-centred medicines optimisation consultation.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Conhecimentos, Atitudes e Prática em Saúde , Adesão à Medicação , Infarto do Miocárdio/tratamento farmacológico , Prevenção Secundária , Inquéritos e Questionários , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Biorretroalimentação Psicológica , Fármacos Cardiovasculares/efeitos adversos , Tomada de Decisão Compartilhada , Deglutição , Embalagem de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Prescrição Inadequada , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/psicologia , Satisfação do Paciente , Valor Preditivo dos Testes , Autorrelato
6.
Open Heart ; 6(2): e000997, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354954

RESUMO

Background: Non-adherence to secondary prevention medicines (SPMs) among patients with coronary artery disease (CAD) remains a challenge in clinical practice. This study attempted to identify actual and potential modifiable barriers to adherence that can be addressed in cardiology clinical practice. Methods: This was a cross-sectional, postal survey-based study of the medicines-taking experience of patients with CAD treated at a secondary/tertiary care centre. All participants had been on SPM for ≥3 months. Results: In total, 696 eligible patients were sent the survey and 503 responded (72.3%). The median age was 70 years, and 403 (80.1%) were male; the median number of individual daily doses of all medicines was 6. The rate of non-adherence to at least one SPM was 43.5% (n=219), but 53.3% of reported non-adherence was to only one SPM. Statins contributed to 66.7% and aspirin to 61.7% of overall non-adherence identified by the Single Question (SQ) tool. In 30.8% of non-adherent patients (n=65), this was at least partly intentional. Barriers included forgetfulness (84.9%; n=186), worry that medicines will do more harm than good (33.8%; n=74), feeling hassled about medicines taking (18.7%; n=41), feeling worse when taking medicines (14.2%; n=31) and not being convinced of the benefit of medicines (9.1%; n=20). In a multivariate analysis, modifiable factors associated with overall non-adherence included being prescribed aspirin (OR: 2.22; 95% CI: 1.18 to 4.17), having specific concern about SPM (OR: 1.12; 95% CI: 1.07 to 1.18) and issues with repeat prescriptions (OR: 2.48; 95% CI: 1.26 to 4.90). Different factors were often associated with intentional versus unintentional non-adherence. Conclusions: Using appropriate self-report tools, patients share actual and potential modifiable barriers to adherence that can be addressed in clinical practice. Non-adherence behaviour was selective. Most non-adherence was driven by forgetfulness, concern about the harm caused by SPM and practical barriers.

7.
Syst Rev ; 7(1): 131, 2018 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-30144828

RESUMO

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not-a phenomenon described as the 'ARB-MI paradox'. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP. METHODS: A comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists (two-tailed p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger's statistic. DISCUSSION: This systematic review will provide a detailed synthesis of evidence regarding the relationship between BP reduction and clinical outcomes with ACEi and ARBs. Greater understanding of the dependency of the effect of each class on BP reduction will advance insight into the nature of the ARB-MI paradox and guide the future usage of these agents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017072988.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Humanos , Infarto do Miocárdio/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
9.
Open Heart ; 5(2): e000921, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613417

RESUMO

Background: Inadequate medicines optimisation and adherence are significant problems among patients taking secondary prevention medications following myocardial infarction (MI). A novel joint consultant cardiology pharmacist and cardiologist medicines optimisation clinic was initiated for patients recently discharged following MI. Methods: Patients completed a locally developed tool, the 'My Experience of Taking Medicines' questionnaire, designed to allow sharing of barriers to adherence with medications. They then attended a clinic with the consultant pharmacist or cardiologist (or both). Secondary prevention medicines needs and barriers to adherence were identified and discussed, and an action plan developed. The data provided are from a retrospective review of 270 post-MI patients attending the service between October 2015 and December 2016. Results: Mean age was 67.3 years and 67.8% were male. The mean time from discharge to first outpatient clinic attendance was reduced by 56.1% (49.4 days vs 88 days before the service began). More than 95% of patient without planned non-pharmacological intervention postdischarge did not need a cardiologist's input. Levels of medicines optimisation were improved substantially after attendance: patients receiving a recommended angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose increased from 16.3% to 73.9% (p<0.001); patients receiving a recommended beta-blocker dose increased from 6.2% to 46.1% (p<0.001). Patient concerns about their medications were significantly decreased (all p<0.001). Rates of non-adherence fell by 42.6%-70.8% at 3-6 months post-clinic. Readmission rates also declined after the service opened. Conclusions: A medicines optimisation and patient adherence strategy based on a joint consultant cardiology pharmacist and cardiologist clinic can improve both adherence and outcomes post-MI.

10.
Can J Diabetes ; 42(2): 124-129, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29277343

RESUMO

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT1) receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all-cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Adulto , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Prognóstico
12.
Circulation ; 135(24): 2336-2353, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28461624

RESUMO

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.


Assuntos
Doença das Coronárias/genética , Doença das Coronárias/prevenção & controle , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Fumar/genética , Proteína ADAMTS7/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Doença das Coronárias/epidemiologia , Vasos Coronários/patologia , Vasos Coronários/fisiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fumar/efeitos adversos , Fumar/epidemiologia
13.
Circ Res ; 121(1): 81-88, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28506971

RESUMO

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Variação Genética/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
14.
JAMA ; 317(9): 937-946, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28267856

RESUMO

Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.


Assuntos
Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Adulto , Idade de Início , Estudos de Casos e Controles , Estudos Transversais , Feminino , Genótipo , Heterozigoto , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Triglicerídeos/sangue
15.
J Am Coll Cardiol ; 68(25): 2761-2772, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-28007139

RESUMO

BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.


Assuntos
Doença das Coronárias/genética , Terapia Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/sangue , Biomarcadores , Doença das Coronárias/sangue , Doença das Coronárias/terapia , DNA/genética , Feminino , Humanos , Lipoproteína(a)/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
16.
Sci Rep ; 6: 35278, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731410

RESUMO

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.


Assuntos
Cromossomos Humanos X , Doença da Artéria Coronariana/genética , Estudos de Coortes , Feminino , Humanos , Internacionalidade , Masculino
18.
N Engl J Med ; 374(22): 2131-41, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27192541

RESUMO

BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).


Assuntos
Receptor de Asialoglicoproteína/genética , Colesterol/sangue , Doença da Artéria Coronariana/genética , Haploinsuficiência , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Islândia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Infarto do Miocárdio/genética , Risco , Análise de Sequência de DNA
19.
Heart ; 102(10): 735-40, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26857212

RESUMO

OBJECTIVE: Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic heart failure. METHODS: Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock. RESULTS: The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria. CONCLUSIONS: TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Técnicas de Apoio para a Decisão , Cardioversão Elétrica/instrumentação , Insuficiência Cardíaca/terapia , Guias de Prática Clínica como Assunto , Idoso , Causas de Morte , Doença Crônica , Desfibriladores Implantáveis/efeitos adversos , Desfibriladores Implantáveis/normas , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/mortalidade , Cardioversão Elétrica/normas , Inglaterra , Feminino , Fidelidade a Diretrizes , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Seleção de Pacientes , Guias de Prática Clínica como Assunto/normas , Modelos de Riscos Proporcionais , Falha de Prótese , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda
20.
Int J Cardiol ; 203: 141-4, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26512829

RESUMO

BACKGROUND: Diabetes mellitus (DM) is an established adverse prognostic factor in patients sustaining myocardial infarction (MI). However, its impact on long-term survival remains less clear. The aim of this observational study was to quantify lifetime mortality and years of life lost after MI in patients with and without DM. METHODS: In 1995, 2153 individuals with MI were recruited from 20 adjacent hospitals within Yorkshire, UK. Median survival, all-cause mortality at 20 years and lost years of life when compared to actuarial predictions were compared in patients with and without DM. Landmark analyses were conducted to define the ongoing impact of DM beyond specified time points. RESULTS: 13% (279/2153) had known DM. They experienced higher mortality at 30 days (33.1% vs 24.6%; p<0.0001) and at 20 years (84.9% vs 75.7%; p<0.0001). Overall, there was a 48% increased risk of death (p<0.0001), which persisted after adjustment for potential confounders. There was no interaction between DM and prior MI in predicting mortality (p=0.67). Median survival decreased by 3.3 years (p<0.0001). The adverse impact of DM persisted in sequential landmark analyses at 1, 5 and 10 years. Presence of DM conferred 2 extra years of life lost when compared with actuarial predictions (8 vs 6 years; p<0.0001). CONCLUSIONS: DM remains an independent adverse prognostic factor in the long-term after MI. Persistently diverging survival curves support enduring efforts to reduce mortality late after MI.


Assuntos
Diabetes Mellitus/mortalidade , Previsões , Infarto do Miocárdio/mortalidade , Sistema de Registros , Medição de Risco/métodos , Adulto , Distribuição por Idade , Idoso , Feminino , Seguimentos , Humanos , Expectativa de Vida/tendências , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida/tendências , Reino Unido/epidemiologia
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