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2.
J Am Heart Assoc ; : e020604, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622670

RESUMO

Background Although the association between dysregulated coagulation and atherosclerosis is well recognized, individual assays have been of minimal value in understanding disease susceptibility. Here we investigated the association of global coagulation profiles with coronary artery disease with consideration of sex differences. Methods and Results The study included patients from the BioHEART-CT (The BioHEART Study: Assessing Patients With Suspected Cardiovascular Disease for New Disease Markers and Risk Factors) biobank who had computed tomography coronary angiograms scored for coronary artery calcium score (CACS) and Gensini score. The cohort included 206 adult patients who were referred for clinically indicated computed tomography coronary angiography and had a median of 2 major cardiac risk factors; 50% were women and the average age was 62.6 years (±9.9 years). The overall hemostatic potential (OHP) and calibrated automated thrombography generation assays were performed on platelet-poor plasma. CACS and Gensini score in men were significantly correlated in bivariate analysis with measures from the OHP assay, and regression models predicting disease severity by CACS or Gensini score were improved by adding the OHP assay variables in men but not in women. The calibrated automated thrombography generation assay demonstrated a more hypercoagulable profile in women than in men. The OHP assay showed hypercoagulable profiles in women with hyperlipidemia and men with obesity. Conclusions The OHP assay identified hypercoagulable profiles associated with different risk factors for each sex and was associated with CACS and Gensini score severity in men, emphasizing the associations between increased fibrin generation and reduced fibrinolysis with cardiac risk factors and early atherosclerosis. Registration Information www.anzctr.org.au. Identifier: ACTRN12618001322224.

3.
BMJ Open ; 11(9): e049858, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34588252

RESUMO

INTRODUCTION: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the ß3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating ß3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. METHODS AND ANALYSIS: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. ETHICS AND DISSEMINATION: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes. TRIAL REGISTRATION NUMBER: ACTRN12619000423112; Results.

4.
Nat Commun ; 12(1): 4992, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404777

RESUMO

Liquid chromatography-mass spectrometry-based metabolomics studies are increasingly applied to large population cohorts, which run for several weeks or even years in data acquisition. This inevitably introduces unwanted intra- and inter-batch variations over time that can overshadow true biological signals and thus hinder potential biological discoveries. To date, normalisation approaches have struggled to mitigate the variability introduced by technical factors whilst preserving biological variance, especially for protracted acquisitions. Here, we propose a study design framework with an arrangement for embedding biological sample replicates to quantify variance within and between batches and a workflow that uses these replicates to remove unwanted variation in a hierarchical manner (hRUV). We use this design to produce a dataset of more than 1000 human plasma samples run over an extended period of time. We demonstrate significant improvement of hRUV over existing methods in preserving biological signals whilst removing unwanted variation for large scale metabolomics studies. Our tools not only provide a strategy for large scale data normalisation, but also provides guidance on the design strategy for large omics studies.


Assuntos
Metabolômica/métodos , Cromatografia Líquida , Humanos , Espectrometria de Massas/métodos , Modelos Biológicos , Fluxo de Trabalho
5.
Atherosclerosis ; 333: 48-55, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34425527

RESUMO

BACKGROUND AND AIMS: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD. METHODS: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis. RESULTS: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001). CONCLUSIONS: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD.

6.
Heart Lung Circ ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34217582

RESUMO

OBJECTIVE: Chest pain is a large health care burden in Australia and around the world. Its management requires specialist assessment and diagnostic tests, which can be costly and often lead to unnecessary hospital admissions. There is a growing unmet clinical need to improve the efficiency and management of chest pain. This study aims to show the cost-benefit of rapid access chest pain clinics (RACC) as an alternative to hospital admission. DESIGN: Retrospective cost-benefit analysis for 12 months. SETTING: RACCs in three Sydney tertiary referral hospitals. MAIN OUTCOME MEASURES: Cost per patient. RESULTS: Hospitals A, B and C implemented RACCs but each operating with slightly different staffing, referral patterns, and diagnostic services. All RACCs had similar costs per patient of AUD$455.25, AUD$427.12 and AUD$474.45, hospitals A, B and C respectively, and similar cost benefits per patient of AUD$1168.75, AUD$1196.88 and AUD$1,149.55, respectively. At least 28%, 26% and 29% of these RACC patients for hospitals A, B, and C, respectively, would have otherwise had to have been admitted to hospital for the model to be cost-beneficial. CONCLUSION: This study shows that a RACC model of care is cost-beneficial in the state of NSW as an alternative strategy to inpatient care for managing chest pain. Scaling up to a national level could represent an even larger benefit for the Australian health system.

8.
Curr Heart Fail Rep ; 18(5): 284-289, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34213729

RESUMO

PURPOSE OF REVIEW: This narrative review synthesizes sex differences in guideline-directed medical therapy (GDMT) use and response among female patients with heart failure with reduced ejection fraction (HFrEF), discusses female representation in HFrEF clinical trials, and outlines future areas of investigation to reduce sex disparities in HFrEF care globally. RECENT FINDINGS: Observational registries suggest sex-specific disparities persist in GDMT rates, and there may be key sex-specific differences in optimal dosing of GDMT in HFrEF patients. Underrepresentation of female patients in HF clinical trials is a key barrier, and sex disparities in HF clinical trial leadership may influence sex-specific knowledge generation of medical management of HFrEF patients. There are important sex-specific differences in GDMT use and response among female HFrEF patients that warrant further study. Increasing female representation in HFrEF clinical trials, diversifying HF trial leadership, and embedding sex-specific approaches in the lifecycle of research from conception to reporting are essential to decreasing sex disparities in clinical care of all HFrEF patients.

9.
Heart Lung Circ ; 30(10): 1442-1448, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34090796

RESUMO

This aim of this paper is to set the scene for the need for impact assessment and return on investment in funded cardiovascular research in Australia, starting with the historical perspective on waste in health and medical research. Recently there has been a substantial move from discussion and policy about the need for research translation, into practice and application via the evolution of funding streams like the Australian Medical Research Future Fund (MRFF). Health and medical research funders play a critical role in both setting the expectations for research translation and impact and helping researchers to meet these expectations. As a leading cause of death, cardiovascular disease is a national health priority, recognised as such with a AUD$220 million MRFF allocation to the Cardiovascular Health Mission. Focussing on cardiovascular research, we address some of the barriers researchers face in prospectively planning for research translation and impact assessment, and call for an ecosystem that supports a return on investment for all stakeholders, especially the community and patient end-users.


Assuntos
Pesquisa Biomédica , Administração Financeira , Austrália/epidemiologia , Ecossistema , Humanos , Pesquisadores
10.
Heart Lung Circ ; 30(10): 1467-1476, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34092503

RESUMO

Cardiovascular diseases (CVD) are leading causes of death and morbidity in Australia and worldwide. Despite improvements in treatment, there remain large gaps in our understanding to prevent, treat and manage CVD events and associated morbidities. This article lays out a vision for enhancing CVD research in Australia through the development of a Big Data system, bringing together the multitude of rich administrative and health datasets available. The article describes the different types of Big Data available for CVD research in Australia and presents an overview of the potential benefits of a Big Data system for CVD research and some of the major challenges in establishing the system for Australia. The steps for progressing this vision are outlined.


Assuntos
Big Data , Doenças Cardiovasculares , Austrália/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Humanos
11.
Circ Res ; 128(12): 1927-1943, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34110900

RESUMO

Peripheral arterial disease is a growing worldwide problem with a wide spectrum of clinical severity and is projected to consume >$21 billion per year in the United States alone. While vascular researchers have brought several therapies to the clinic in recent years, few of these approaches have leveraged advances in high-throughput discovery screens, novel translational models, or innovative trial designs. In the following review, we discuss recent advances in unbiased genomics and broader omics technology platforms, along with preclinical vascular models designed to enhance our understanding of disease pathobiology and prioritize targets for additional investigation. Furthermore, we summarize novel approaches to clinical studies in subjects with claudication and ischemic ulceration, with an emphasis on streamlining and accelerating bench-to-bedside translation. By providing a framework designed to enhance each aspect of future clinical development programs, we hope to enrich the pipeline of therapies that may prevent loss of life and limb for those with peripheral arterial disease.

13.
Atherosclerosis ; 333: 100-107, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34045070

RESUMO

BACKGROUND AND AIMS: Targeting the modifiable risk factors for coronary artery disease (CAD) has substantial impact at the community level. However, it is not uncommon for individuals to present with atherosclerosis related events without identified risk factors. We examined sex differences in the association of risk factors and atherosclerotic burden assessed by CT coronary angiography (CTCA). METHODS: We analysed clinical and imaging data in 1002 individuals in the BioHEART cohort. RESULTS: 45% were female, 35% had no CAD identified. Median coronary calcium score was 9.9 Agatston units (IQR: 0-146), and median Gensini Score was 3.5 (IQR: 0-11.5). 26% had a calcified plaque predominant phenotype, and 18% had a non-calcified plaque predominant phenotype. There were no sex differences in the prevalence of risk factors. However, there were notable sex differences in the adjusted associations of risk factors with CAD. Age and hypercholesterolaemia (OR 1.56, 95% CI 1.03-2.36, p = 0.04 in males, and OR 1.75, 95% CI 1.09-2.78, p = 0.02 in females) were associated with the presence of CAD in both genders (p < 0.05). Diabetes and smoking were associated with presence of CAD, calcified CAD, and non-calcified plaque in males (p < 0.05) but not females. In women, none of the standard modifiable risk factors were associated with the amount of plaque present when adjusted for age, BMI, and family history of premature CAD. CONCLUSIONS: CTCA provides an important opportunity for improving the stratification of cohorts to assess underlying biology and risk. We demonstrate sex-specific differences in associations of risk factors with atherosclerosis burden.

17.
Lancet ; 397(10292): 2385-2438, 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010613

RESUMO

Cardiovascular disease is the leading cause of death in women. Decades of grassroots campaigns have helped to raise awareness about the impact of cardiovascular disease in women, and positive changes affecting women and their health have gained momentum. Despite these efforts, there has been stagnation in the overall reduction of cardiovascular disease burden for women in the past decade. Cardiovascular disease in women remains understudied, under-recognised, underdiagnosed, and undertreated. This Commission summarises existing evidence and identifies knowledge gaps in research, prevention, treatment, and access to care for women. Recommendations from an international team of experts and leaders in the field have been generated with a clear focus to reduce the global burden of cardiovascular disease in women by 2030. This Commission represents the first effort of its kind to connect stakeholders, to ignite global awareness of sex-related and gender-related disparities in cardiovascular disease, and to provide a springboard for future research.

18.
Circulation ; 144(2): 159-169, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-33876947

RESUMO

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

19.
Cells ; 10(5)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922315

RESUMO

Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12-1.79, p = 0.004), calcified plaque, and obstructive CAD (p < 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02-0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09-2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04-0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23-1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01-3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53-0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26-2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59-3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14-0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level.

20.
Eur Heart J ; 42(15): 1464-1475, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33847746

RESUMO

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.


Assuntos
Doenças Cardiovasculares , Preparações Farmacêuticas , Biomarcadores , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Descoberta de Drogas , Humanos
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