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Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long-term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow-up, 6 years) and long-term (median follow-up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR-creatinine, then GFR-creatinine-cystatin C). Over 6 years, in fully adjusted multivariable time-to-event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07-1.74; P=0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19-1.82; P<0.001). Over 16 years, the association of baseline cystatin C with coronary heart disease, cardiovascular, and all-cause mortality persisted (each P<0.001) and remained significant after adjustment for estimated GFR-creatinine-cystatin C. Cystatin C also predicted the development of chronic kidney disease for 6 years (odds ratio, 6.61; 95% CI, 4.28-10.20) independently of estimated GFR-creatinine and other risk factors. However, this association was no longer significant after adjustment for estimated GFR-creatinine-cystatin C. Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all-cause mortality. Prediction of long-term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au; Unique identifier: A

Background The plasma concentration of B-type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured. Methods and Results Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient-years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1-year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1-year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44-1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44-1.60]), and years 10-16 (HR, 1.43 [95% CI, 1.36-1.50]), P<0.0001 for all. Conclusions BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long-term risk prediction.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits

OBJECTIVE: To construct a whole-of-system model to inform strategies that reduce the burden of cardiovascular disease (CVD) in Australia. METHODS: A system dynamics model was developed with a multidisciplinary modelling consortium. The model population comprised Australians aged 40 years and over, and the scope encompassed acute and chronic CVD as well as primary and secondary prevention. Health outcomes were CVD-related deaths and hospitalisations, and economic outcomes were the net benefit from both the healthcare system and societal perspectives. The eight strategies broadly included creating social and physical environments supportive of a healthy lifestyle, increasing the use of preventive treatments, and improving systems response to acute CVD events. The effects of strategies were estimated as relative differences to the business-as-usual between 2019-2039. Probabilistic sensitivity analysis produced uncertainty intervals of interquartile ranges (IQR). FINDINGS: The greatest reduction in CVD-related deaths was seen in strategies that improve systems response to acute CVD events (8.9%, IQR: 7.7-10.2%), yet they resulted in an increase in CVD-related hospitalisations due to future recurrent admissions (1.6%, IQR: 0.1-2.3%). This flow-on effect highlighted the importance of addressing underlying CVD risks. On the other hand, strategies targeting the broad environment that supports a healthy lifestyle were effective in reducing both hospitalisations (7.1%; IQR: 5.0-9.5%) and deaths (8.1% reduction; IQR: 7.1-8.9%). They also produced an economic net benefit of AU$43.3 billion (IQR: 37.7-48.7) using a societal perspective, largely driven by productivity gains. Overall, strategic planning to reduce the burden of CVD should consider the varying effects of strategies over time and beyond the health sector.

OBJECTIVES: Describe the incidence of cardiac complications in patients admitted to hospital with COVID-19 in Australia. DESIGN: Observational cohort study. SETTING: Twenty-one (21) Australian hospitals. PARTICIPANTS: Consecutive patients aged ≥18 years admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MAIN OUTCOME MEASURES: Incidence of cardiac complications. RESULTS: Six-hundred-and-forty-four (644) hospitalised patients (62.5±20.1 yo, 51.1% male) with COVID-19 were enrolled in the study. Overall in-hospital mortality was 14.3%. Twenty (20) (3.6%) patients developed new atrial fibrillation or flutter during admission and 9 (1.6%) patients were diagnosed with new heart failure or cardiomyopathy. Three (3) (0.5%) patients developed high grade atrioventricular (AV) block. Two (2) (0.3%) patients were clinically diagnosed with pericarditis or myopericarditis. Among the 295 (45.8%) patients with at least one troponin measurement, 99 (33.6%) had a peak troponin above the upper limit of normal (ULN). In-hospital mortality was higher in patients with raised troponin (32.3% vs 6.1%, p<0.001). New onset atrial fibrillation or flutter (6.4% vs 1.0%, p=0.001) and troponin elevation above the ULN (50.3% vs 16.4%, p<0.001) were more common in patients 65 years and older. There was no significant difference in the rate of cardiac complications between males and females. CONCLUSIONS: Among patients with COVID-19 requiring hospitalisation in Australia, troponin elevation was common but clinical cardiac sequelae were uncommon. The incidence of atrial arrhythmias and troponin elevation was greatest in patients 65 years and older.

OBJECTIVE: To assess whether hypertension is an independent risk factor for mortality among patients hospitalised with COVID-19, and to evaluate the impact of ACE inhibitor and angiotensin receptor blocker (ARB) use on mortality in patients with a background of hypertension. METHOD: This observational cohort study included all index hospitalisations with laboratory-proven COVID-19 aged ≥18 years across 21 Australian hospitals. Patients with suspected, but not laboratory-proven COVID-19, were excluded. Registry data were analysed for in-hospital mortality in patients with comorbidities including hypertension, and baseline treatment with ACE inhibitors or ARBs. RESULTS: 546 consecutive patients (62.9±19.8 years old, 51.8% male) hospitalised with COVID-19 were enrolled. In the multivariable model, significant predictors of mortality were age (adjusted OR (aOR) 1.09, 95% CI 1.07 to 1.12, p<0.001), heart failure or cardiomyopathy (aOR 2.71, 95% CI 1.13 to 6.53, p=0.026), chronic kidney disease (aOR 2.33, 95% CI 1.02 to 5.32, p=0.044) and chronic obstructive pulmonary disease (aOR 2.27, 95% CI 1.06 to 4.85, p=0.035). Hypertension was the most prevalent comorbidity (49.5%) but was not independently associated with increased mortality (aOR 0.92, 95% CI 0.48 to 1.77, p=0.81). Among patients with hypertension, ACE inhibitor (aOR 1.37, 95% CI 0.61 to 3.08, p=0.61) and ARB (aOR 0.64, 95% CI 0.27 to 1.49, p=0.30) use was not associated with mortality. CONCLUSIONS: In patients hospitalised with COVID-19, pre-existing hypertension was the most prevalent comorbidity but was not independently associated with mortality. Similarly, the baseline use of ACE inhibitors or ARBs had no independent association with in-hospital mortality.

Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits

The global coronavirus disease (COVID-19) pandemic poses an unprecedented stress on healthcare systems internationally. These Health system-wide demands call for efficient utilisation of resources at this time in a fair, consistent, ethical and efficient manner would improve our ability to treat patients. Excellent co-operation between hospital units (especially intensive care unit [ICU], emergency department [ED] and cardiology) is critical in ensuring optimal patient outcomes. The purpose of this document is to provide practical guidelines for the effective use of interventional cardiology services in Australia and New Zealand. The document will be updated regularly as new evidence and knowledge is gained with time. Goals 1. Efficient use of resources (including staff, personal protective equipment [PPE]) 2. Direct interventional cardiology use towards the highest yield use of hospital capacity 3. Minimise adverse patient outcomes 4. Minimise risk to healthcare workers. Considerations 1. Fibrinolysis may be considered (or even preferred) in ST segment elevation myocardial infarction (STEMI) reperfusion in hospitals even with catheter laboratories 2. Postponement of non-urgent procedures to reduce demand on beds, use of PPE, staff and other resources 3. Postpone invasive angiography in “stable” ischaemic heart disease patients 4. Postpone non-urgent transcatheter aortic valve implantation (TAVI) and Mitra-clipTM and all atrial septal defect (ASD)/patent foramen ovale (PFO) and left atrial appendage (LAA) closure procedures 5. In health care networks, centralisation of primary angioplasty services may be possible 6. Training of staff in proper PPE donning and doffing is mandatory 7. Fragmentation of staff into teams is desirable and can mitigate risk of exposure and impact on staffing levels to a degree 8. Working closely with ED, ICU and anaesthetics services from planning to processes promotes efficiency and reduces stress in practice.

Introduction: The coronavirus 2019 disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pre-existing cardiovascular disease (CVD) increases the morbidity and mortality of COVID-19, and COVID-19 itself causes serious cardiac sequelae. Strategies to minimise the risk of viral transmission to health care workers and uninfected cardiac patients while prioritising high quality cardiac care are urgently needed. We conducted a rapid literature appraisal and review of key documents identified by the Cardiac Society of Australia and New Zealand Board and Council members, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, and key cardiology, surgical and public health opinion leaders. Main recommendations: Common acute cardiac manifestations of COVID-19 include left ventricular dysfunction, heart failure, arrhythmias and acute coronary syndromes. The presence of underlying CVD confers a five- to tenfold higher case fatality rate with COVID-19 disease. Special precautions are needed to avoid viral transmission to this population at risk. Adaptive health care delivery models and resource allocation are required throughout the health care system to address this need. Changes in management as a result of this statement: Cardiovascular health services and cardiovascular health care providers need to recognise the increased risk of COVID-19 among CVD patients, upskill in the management of COVID-19 cardiac manifestations, and reorganise and innovate in service delivery models to meet demands. This consensus statement, endorsed by the Cardiac Society of Australia and New Zealand, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, the National Heart Foundation of Australia and the High Blood Pressure Research Council of Australia summarises important issues and proposes practical approaches to cardiovascular health care delivery to patients with and without SARS-CoV-2 infection.Copyright © 20

Introduction: The coronavirus 2019 disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pre-existing cardiovascular disease (CVD) increases the morbidity and mortality of COVID-19, and COVID-19 itself causes serious cardiac sequelae. Strategies to minimise the risk of viral transmission to health care workers and uninfected cardiac patients while prioritising high quality cardiac care are urgently needed. We conducted a rapid literature appraisal and review of key documents identified by the Cardiac Society of Australia and New Zealand Board and Council members, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, and key cardiology, surgical and public health opinion leaders. Main recommendations: Common acute cardiac manifestations of COVID-19 include left ventricular dysfunction, heart failure, arrhythmias and acute coronary syndromes. The presence of underlying CVD confers a five- to tenfold higher case fatality rate with COVID-19 disease. Special precautions are needed to avoid viral transmission to this population at risk. Adaptive health care delivery models and resource allocation are required throughout the health care system to address this need. Changes in management as a result of this statement: Cardiovascular health services and cardiovascular health care providers need to recognise the increased risk of COVID-19 among CVD patients, upskill in the management of COVID-19 cardiac manifestations, and reorganise and innovate in service delivery models to meet demands. This consensus statement, endorsed by the Cardiac Society of Australia and New Zealand, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, the National Heart Foundation of Australia and the High Blood Pressure Research Council of Australia summarises important issues and proposes practical approaches to cardiovascular health care delivery to patients with and without SARS-CoV-2 infection.Copyright © 20

The global coronavirus disease (COVID-19) pandemic poses an unprecedented stress on healthcare systems internationally. These Health system-wide demands call for efficient utilisation of resources at this time in a fair, consistent, ethical and efficient manner would improve our ability to treat patients. Excellent co-operation between hospital units (especially intensive care unit [ICU], emergency department [ED] and cardiology) is critical in ensuring optimal patient outcomes. The purpose of this document is to provide practical guidelines for the effective use of interventional cardiology services in Australia and New Zealand. The document will be updated regularly as new evidence and knowledge is gained with time. Goals Considerations.

INTRODUCTION: The coronavirus 2019 disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pre-existing cardiovascular disease (CVD) increases the morbidity and mortality of COVID-19, and COVID-19 itself causes serious cardiac sequelae. Strategies to minimise the risk of viral transmission to health care workers and uninfected cardiac patients while prioritising high quality cardiac care are urgently needed. We conducted a rapid literature appraisal and review of key documents identified by the Cardiac Society of Australia and New Zealand Board and Council members, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, and key cardiology, surgical and public health opinion leaders. MAIN RECOMMENDATIONS: Common acute cardiac manifestations of COVID-19 include left ventricular dysfunction, heart failure, arrhythmias and acute coronary syndromes. The presence of underlying CVD confers a five- to tenfold higher case fatality rate with COVID-19 disease. Special precautions are needed to avoid viral transmission to this population at risk. Adaptive health care delivery models and resource allocation are required throughout the health care system to address this need. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Cardiovascular health services and cardiovascular health care providers need to recognise the increased risk of COVID-19 among CVD patients, upskill in the management of COVID-19 cardiac manifestations, and reorganise and innovate in service delivery models to meet demands. This consensus statement, endorsed by the Cardiac Society of Australia and New Zealand, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, the National Heart Foundation of Australia and the High Blood Pressure Research Council of Australia summarises important issues and proposes practical approaches to cardiovascular health care delivery to patients with and without SARS-CoV-2 infection.

Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy. Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure. Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing. This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE). The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients.

Introduction

Main recommendations

Changes in management as a result of this statement

Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy. Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure. Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing. This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE). The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients.

Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy. Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure. Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing. This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE). The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients.

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

© 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ) Background: Increased access to reperfusion for ST elevation myocardial infarction (STEMI) has contributed to reduced mortality internationally. We describe temporal trends in pre-hospital care, in-hospital management and outcomes of the STEMI population in Australia. Methods: Temporal trends with multiple regression analysis on the management and outcomes of STEMI patients enrolled across 46 Australian hospitals in the Australian cohort of the Global Registry of Acute Coronary Events (GRACE) and the Cooperative National Registry of Acute Coronary Care Guideline Adherence and Clinical Events (CONCORDANCE) between February 1999 and August 2016. Results: 4,110 patients were treated for STEMI, mean age 62.5 ± 13.7years (SD). The median door-to-balloon time of primary percutaneous coronary intervention (PPCI) decreased by 11 minutes (p < 0.01) although there was no increase in rates of PPCI (p = 0.35). Access to non-primary PCI increased by 39% (p < 0.01), provisioning of fibrinolysis decreased by 13% (p < 0.01) and the median door-to-needle time of 35 minutes remained unchanged (p = 0.09). Prescription of medical therapies in-hospital remained high, and at discharge there was an increase in prescription of statins (p < 0.01); aspirin including antiplatelets (p < 0.01), beta blockers (p = 0.023) and ACE/ARB (p = 0.02). The occurrence of any in-hospital adverse clinical events declined by 78% (p < 0.01) albeit, there was no reduction in mortality in-hospital (p = 0.84) or within 6 months (p = 0.81). Conclusions: Over time, there has been increased access to non-primary PCI; shorter door-to-balloon times for PPCI; less adverse events in-hospital and fewer readmissions for unplanned revascularisation without the realisation of reduced mortality in-hospital or at 6 months. Trial registration: CONCORDANCE Registry ACTRN: 1261400088

© 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ) Background: Increased access to reperfusion for ST elevation myocardial infarction (STEMI) has contributed to reduced mortality internationally. We describe temporal trends in pre-hospital care, in-hospital management and outcomes of the STEMI population in Australia. Methods: Temporal trends with multiple regression analysis on the management and outcomes of STEMI patients enrolled across 46 Australian hospitals in the Australian cohort of the Global Registry of Acute Coronary Events (GRACE) and the Cooperative National Registry of Acute Coronary Care Guideline Adherence and Clinical Events (CONCORDANCE) between February 1999 and August 2016. Results: 4,110 patients were treated for STEMI, mean age 62.5 ± 13.7years (SD). The median door-to-balloon time of primary percutaneous coronary intervention (PPCI) decreased by 11 minutes (p < 0.01) although there was no increase in rates of PPCI (p = 0.35). Access to non-primary PCI increased by 39% (p < 0.01), provisioning of fibrinolysis decreased by 13% (p < 0.01) and the median door-to-needle time of 35 minutes remained unchanged (p = 0.09). Prescription of medical therapies in-hospital remained high, and at discharge there was an increase in prescription of statins (p < 0.01); aspirin including antiplatelets (p < 0.01), beta blockers (p = 0.023) and ACE/ARB (p = 0.02). The occurrence of any in-hospital adverse clinical events declined by 78% (p < 0.01) albeit, there was no reduction in mortality in-hospital (p = 0.84) or within 6 months (p = 0.81). Conclusions: Over time, there has been increased access to non-primary PCI; shorter door-to-balloon times for PPCI; less adverse events in-hospital and fewer readmissions for unplanned revascularisation without the realisation of reduced mortality in-hospital or at 6 months. Trial registration: CONCORDANCE Registry ACTRN: 1261400088

© The Author 2016. Aims Acute coronary syndrome (ACS) is a costly condition for health service provision yet variation in the delivery of care between hospitals persists. A composite measure of adherence with evidence-based clinical-process indicators (CPIs) could better inform hospital performance reporting and clinical outcomes in the management of ACS. Methods Data on 7444 ACS patients from 39 Australian hospitals were used to derive a hospital-specific composite quality score by calculating mean adherence to 14 evidence-based CPIs. Using the generalized estimating equation to account for clustering of patients within hospitals and the GRACE risk score to adjust for differences in presenting risk, we evaluated associations between the hospital-specific composite quality score, in-hospital major adverse events, in-hospital mortality and mortality and readmission for ACS at 6 months. Results Hospitals had a mean adherence of 68.3% (SD 21.7) with the composite quality score. There was significant variation between hospital adherence tertile 1 (79%) and tertile 3 (56%), P, 0.0001. With risk adjustment, there was an association between hospitals with a higher composite quality score and reduced in-hospital adverse events (OR: 0.85, CI: 0.71 - 0.99) and survival at hospital discharge (OR: 0.47; 95% CI: 0.28 - 0.77). There was trending improvement in survival at 6 months (OR 0.48; CI: 0.20 - 1.16) and fewer readmissions to hospital for ACS at 6 months (OR 0.79; CI 0.60 - 1.05). Conclusion The association between the quality composite score and reduced in-hospital events and survival at hospital discharge supports the utility of reporting CPIs in routine hospital performance reporting on the management of ACS.

© The Author 2016. Aims Acute coronary syndrome (ACS) is a costly condition for health service provision yet variation in the delivery of care between hospitals persists. A composite measure of adherence with evidence-based clinical-process indicators (CPIs) could better inform hospital performance reporting and clinical outcomes in the management of ACS. Methods Data on 7444 ACS patients from 39 Australian hospitals were used to derive a hospital-specific composite quality score by calculating mean adherence to 14 evidence-based CPIs. Using the generalized estimating equation to account for clustering of patients within hospitals and the GRACE risk score to adjust for differences in presenting risk, we evaluated associations between the hospital-specific composite quality score, in-hospital major adverse events, in-hospital mortality and mortality and readmission for ACS at 6 months. Results Hospitals had a mean adherence of 68.3% (SD 21.7) with the composite quality score. There was significant variation between hospital adherence tertile 1 (79%) and tertile 3 (56%), P, 0.0001. With risk adjustment, there was an association between hospitals with a higher composite quality score and reduced in-hospital adverse events (OR: 0.85, CI: 0.71 - 0.99) and survival at hospital discharge (OR: 0.47; 95% CI: 0.28 - 0.77). There was trending improvement in survival at 6 months (OR 0.48; CI: 0.20 - 1.16) and fewer readmissions to hospital for ACS at 6 months (OR 0.79; CI 0.60 - 1.05). Conclusion The association between the quality composite score and reduced in-hospital events and survival at hospital discharge supports the utility of reporting CPIs in routine hospital performance reporting on the management of ACS.

The prognostic significance of patients presenting with pulmonary embolism (PE) and elevated International Normalised Ratio (INR) not on anticoagulant therapy has not been described. We investigated whether these patients had higher mortality compared to patients with normal INR. A retrospective study of patients admitted to a tertiary hospital with acute PE from 2000 to 2012 was undertaken, with study outcomes tracked using a state-wide death registry. Patients were excluded if they were taking anticoagulants or had inadequate documentation of their INR and medication status. Of the 1,039 patients identified, 94 (9 %) had an elevated INR (> 1.2) in the absence of anticoagulant use. These patients had higher mortality at six months follow-up (26 % vs 6 %, p< 0.001) compared to controls (INR ≤ 1.2). An INR > 1.2 at diagnosis was an independent predictor of death at six months post-PE (hazard ratio [HR] 2.9, 95 % confidence interval [CI] 1.8–4.7, p< 0.001). The addition of INR to a multivariable model that included the simplified pulmonary embolism severity index (sPESI), chest pain, and serum sodium led to a significant net reclassification improvement estimated at 8.1 %. The final model’s C statistic increased significantly by 0.04 (95 % CI 0.01–0.08, p=0.03) to 0.83 compared to sPESI alone (0.79). In summary, patients presenting with acute PE and elevated INR while not on anticoagulant therapy appear to be at high risk of death. Future validation studies in independent cohorts will clarify if this novel finding can be usefully incorporated into clinical decision making in patients with acute PE.

© 2016 Bing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Acute pulmonary embolism (PE) carries an increased risk of death. Using transthoracic echocardiography (TTE) to assist diagnosis and risk stratification is recommended in current guidelines. However, its utilization in real-world clinical practice is unknown. We conducted a retrospective observational study to delineate the prevalence of inpatient TTE use following confirmed acute PE, identify predictors for its use and its impact on patient's outcome. Methods Clinical details of consecutive patients (2000 to 2012) from two tertiary-referral hospitals were retrieved from dedicated PE databases. All-cause and cause-specific mortality was tracked from a state-wide death registry. Results In total, 2306 patients were admitted with confirmed PE, of whom 687 (29.8%) had inpatient TTE (39.3% vs 14.4% between sites, P<0.001). Site to which patient presented, older age, cardiac failure, atrial fibrillation and diabetes were independent predictors for inpatient TTE use, while malignancy was a negative predictor. Overall mortality was 41.4% (mean followup 66.5±49.5months). Though inpatient TTE use was not an independent predictor for allcause or cardiovascular mortality in multivariable analysis, in the inpatient TTE subgroup, right ventricle-right atrial pressure gradient (hazard ratio [HR] 1.02 per-1mmHg increase, 95% confidence interval [CI] 1.01-1.03) and moderate/severe aortic stenosis (HR 2.26, 95% CI 1.20-4.27) independently predicted all-cause mortality. Conclusions Inpatient TTE is used infrequently in real-world clinical settings following acute PE despite its usefulness in risk stratification, prognostication and assessing comorbid cardiac pathologies. Identifying patients that will benefit most from a T

Background and objectives:We documented treatment and outcomes of Culturally and Linguistically Diverse (CALD) patients from the CONCORDANCE investigator initiated acute coronary syndromes (ACS) registry. Method(s): Of 1500 subjects from 17 sites, we analysed cardiovascular outcomes and usage of evidence-based therapies according to region of origin and whether the subject reported English as their second language (ESL). Result(s): Region of origin was 1033 from Australia/New Zealand, 99 Asian, 127 UK/USA, 144 European and 97 African/Other. Three hundred (20%) reported ESL. English speakers (ES) were older 63.3+/-13.2 versus 59.4+/-15.4 years (p < 0.001) and had less diabetes mellitus (24.4% vs. 41.2%, p < 0.001) and smoking (31.8% vs. 45.4%, p < 0.001), but similar previous MI and heart failure rates. At 479 days, all cause death (4.3% vs. 2.0%; p = 0.03) was higher among the ESL cohort. All cause death and MI were 7.3% (ESL) vs. 5.6% (ES; p = 0.281). After adjusting for GRACE score and diabetes, ESL had a hazard ratio of 1.88 (95% C.I. 0.95-3.74, p = 0.07) for increased mortality. Cardiac catheterisation (77% vs. 82%; p = 0.03) and percutaneous coronary intervention (37% vs. 49%; p = 0.001) rates were lower in the ESL group. At discharge, use of ACE inhibitors (62% vs. 64%, p = 0.54); clopidogrel (65% vs. 62%, p = 0.224); aspirin (86% vs. 88%; p = 0.23) and betablockers (80% vs. 76%; p = 0.132) were similar in ES and ESL groups but statin usage was less in the ESL group (88% vs. 93%; p = 0.01). Conclusion(s): Patients inwhompatients report ESL have a worse outcome after presenting with ACS.

Background and objectives:We documented treatment and outcomes of Culturally and Linguistically Diverse (CALD) patients from the CONCORDANCE investigator initiated acute coronary syndromes (ACS) registry. Method(s): Of 1500 subjects from 17 sites, we analysed cardiovascular outcomes and usage of evidence-based therapies according to region of origin and whether the subject reported English as their second language (ESL). Result(s): Region of origin was 1033 from Australia/New Zealand, 99 Asian, 127 UK/USA, 144 European and 97 African/Other. Three hundred (20%) reported ESL. English speakers (ES) were older 63.3+/-13.2 versus 59.4+/-15.4 years (p < 0.001) and had less diabetes mellitus (24.4% vs. 41.2%, p < 0.001) and smoking (31.8% vs. 45.4%, p < 0.001), but similar previous MI and heart failure rates. At 479 days, all cause death (4.3% vs. 2.0%; p = 0.03) was higher among the ESL cohort. All cause death and MI were 7.3% (ESL) vs. 5.6% (ES; p = 0.281). After adjusting for GRACE score and diabetes, ESL had a hazard ratio of 1.88 (95% C.I. 0.95-3.74, p = 0.07) for increased mortality. Cardiac catheterisation (77% vs. 82%; p = 0.03) and percutaneous coronary intervention (37% vs. 49%; p = 0.001) rates were lower in the ESL group. At discharge, use of ACE inhibitors (62% vs. 64%, p = 0.54); clopidogrel (65% vs. 62%, p = 0.224); aspirin (86% vs. 88%; p = 0.23) and betablockers (80% vs. 76%; p = 0.132) were similar in ES and ESL groups but statin usage was less in the ESL group (88% vs. 93%; p = 0.01). Conclusion(s): Patients inwhompatients report ESL have a worse outcome after presenting with ACS.

Background: Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. Method(s): The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. Conclusion(s): The CONCORDANCE registry is a clinician-drive

Background: Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. Method(s): The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. Conclusion(s): The CONCORDANCE registry is a clinician-drive

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

Background: The Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an observational registry reporting temporal trends in the management of acute coronary syndromes (ACS). System level factors impacting this care are described with clinical and epidemiological sub-studies, including an Aboriginal and Torres Strait Islander initiative and a biomarker data bank. Method(s): Patient's with an ST elevation myocardial infarction (STEMI),non ST elevation myocardial infarction (NSTEMI) and those considered high risk for anACS event are eligible for inclusion. The 16 participating Australian centres are located in geographically different regions and represent services provided in these locations. Data are returned to the sites in a real-time confidential report including 20 Key Primary Indicator (KPI) process measures, patient demographics, in-hospital management and outcomes at six months and two years. Aggregated data for the entire cohort are presented for comparison with local site performance. Current results: 901patients are enrolled with a median age of 62 yrs+/-13.7 and a mean GRACE risk score of 129. 563 (62.5%) are males. Overall 633 (70.3%) of ACS patients undergo in-hospital cath, 56.5% of patients are discharged on appropriate medical therapy and 505 (56%) of this ACS cohort are referred to cardiac rehabilitation. Conclusion(s): The CONCORDANCE Registry provides clinicians with performance measures for management of ACS. The participating centres reflect the diversity in services around the country and are associated with important variations in clinical practice. Documenting and understanding these variations will provide opportunities to improve processes of care nationally. (Figure presented).

Background: The Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an observational registry reporting temporal trends in the management of acute coronary syndromes (ACS). System level factors impacting this care are described with clinical and epidemiological sub-studies, including an Aboriginal and Torres Strait Islander initiative and a biomarker data bank. Method(s): Patient's with an ST elevation myocardial infarction (STEMI),non ST elevation myocardial infarction (NSTEMI) and those considered high risk for anACS event are eligible for inclusion. The 16 participating Australian centres are located in geographically different regions and represent services provided in these locations. Data are returned to the sites in a real-time confidential report including 20 Key Primary Indicator (KPI) process measures, patient demographics, in-hospital management and outcomes at six months and two years. Aggregated data for the entire cohort are presented for comparison with local site performance. Current results: 901patients are enrolled with a median age of 62 yrs+/-13.7 and a mean GRACE risk score of 129. 563 (62.5%) are males. Overall 633 (70.3%) of ACS patients undergo in-hospital cath, 56.5% of patients are discharged on appropriate medical therapy and 505 (56%) of this ACS cohort are referred to cardiac rehabilitation. Conclusion(s): The CONCORDANCE Registry provides clinicians with performance measures for management of ACS. The participating centres reflect the diversity in services around the country and are associated with important variations in clinical practice. Documenting and understanding these variations will provide opportunities to improve processes of care nationally. (Figure presented).

Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.

Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.

Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.

Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process. © The Authors Journal compilation.

Glycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their Separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. (c) 2006 Elsevier Inc. All rights reserved.

Glycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their Separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. (c) 2006 Elsevier Inc. All rights reserved.

Glycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their Separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. (c) 2006 Elsevier Inc. All rights reserved.

Glycosylation is a common but variable modification that regulates glycoprotein structure and function. We combined small format 2D-PAGE with HPLC to analyse discrete human haptoglobin isoform N-glycans. Seven major and several minor haptoglobin isoforms were detected by 2D-PAGE. N-Glycans released from Coomassie-stained gel spots using PNGase were labeled at their reducing termini with 2-aminobenzamide. HPLC analysis of selected major isoform N-glycans indicated that sialic acid composition determined their Separation by isoelectric focussing. N-Glycans from two doublets of quantitatively minor isoforms were also analysed. Although separation of each pair of doublets was influenced by sialylation, individual spots within each doublet contained identical N-glycans. Thus, heterogeneity in minor haptoglobin isoforms was due to modifications distinct from N-glycan structure. These studies describe a simple method for analysing low abundance protein N-glycans and provide details of discrete haptoglobin isoform N-glycan structures which will be useful in proteomic analysis of human plasma samples. (c) 2006 Elsevier Inc. All rights reserved.

CYP27A1 (sterol 27-hydroxylase) catalyses an important sterol elimination pathway in the human macrophage, and consequently may protect against atherosclerosis. We studied the expression and regulation of CYP27A1 in a human macrophage-like cell-line, THP-1, and primary HMDMs (human monocyte-derived macrophages). In both macrophage cell types, we found that CYP27A1 expression is independent of cellular cholesterol levels and of LXR (liver X receptor)-dependent control of transcription. However, the RXR (retinoid X receptor) ligand, 9-cis-retinoic acid, upregulates CYP27A1 expression. Of the RXR heterodimeric partners tested, PPAR (peroxisome-proliferator-activated receptor) γ ligands significantly increased CYP27A1 mRNA levels. Its reversal by a PPARγ antagonist demonstrated the specificity of this effect. Interestingly, HMDMs express markedly higher levels of CYP27A1 than THP-1 macrophages, and this difference was reflected in both protein levels and enzyme activities between the two cell types. In conclusion, stimulation of CYP27A1 by PPARγ may represent a key previously unrecognized mechanism by which PPARγ protects against atherosclerosis.

Objective: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. Research design and methods: FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. Results: About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI >30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement (41%), high waist measurement (65%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). Conclusion: The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic

Background: Fibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting. Methods: Subjects with type 2 diabetes, aged 50-75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0-6.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol /L with no clear indication for lipid-modifying therapy were eligible. Results: A total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods. Conclusions: Type 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.