Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial.

BACKGROUND: Low-dose colchicine significantly reduces the risk of cardiovascular events in patients with chronic coronary disease. An increase of non-cardiovascular death raised concerns about its safety. This study reports cause-specific mortality and baseline predictors of mortality in the Low-Dose Colchicine 2 (LoDoCo2) trial. METHODS: Patients with chronic coronary disease were randomly allocated to colchicine 0.5 mg once daily or placebo on a background of optimal medical therapy. Cause-specific mortality data were analysed, stratified by treatment status. Multivariate analyses were performed to examine the predictors of mortality as well as cardiovascular and non-cardiovascular death. RESULTS: After a median 28.6 months follow-up, 133 out of 5522 participants (2.4%) died. Forty-five deaths were cardiovascular (colchicine versus placebo: 20 [0.7%] versus 25 [0.9%], HR, 0.80; 95% CI, 0.44-1.44), while eighty-eight deaths were non-cardiovascular (53 [1.9%] versus 35 [1.3%]; HR, 1.51; 95% CI, 0.99-2.31). Forty-eight deaths were due to cancer (26 [0.9%] versus 22 [0.8%]), thirteen end-stage pulmonary disease (9 [0.3%] versus 4 [0.1%]), eight infection (4 [0.1%] versus 4 [0.1%]), five dementia (4 [0.1%] versus 1 [0.0%]) and five related multiple organ failure (3 [0.1%] versus 2 [0.1%]). Multivariable analysis demonstrated age > 65 years was the only independent baseline characteristic associated with non-cardiovascular death (HR, 3.65; 95% CI, 2.06-6.47). CONCLUSIONS: During the LoDoCo2 trial, assignment to colchicine was not associated with an adverse effect on any specific causes of death. Most deaths were related to non-cardiovascular causes, underscoring the importance of comorbidities as drivers of all-cause mortality in patients with chronic coronary disease.

Consensus Statement Regarding the Efficacy and Safety of Long-Term Low-Dose Colchicine in Gout and Cardiovascular Disease.

Over the last decade, evidence has demonstrated that long-term, low-dose colchicine (0.5 mg daily) is effective for preventing gout flare and cardiovascular (CV) events in a wide range of patients. Given the potentially expanding use of colchicine in CV disease, we here review and update the biologic effects and safety of colchicine based on recent data gathered from bench and pharmacodynamic studies, clinical reports, controlled clinical trials, and meta-analyses, integrated with important studies over the last 50 years, to offer a consensus perspective by experts from multiple specialties familiar with colchicine's long-term use. We conclude that the clinical benefits of colchicine in gout and CV disease achieved at low dose do not sustain serum levels above the upper limit of safety when used in patients without advanced renal or liver disease or when used concomitantly with most medications. Further, data accrued over the last 50 years strongly suggest that the biologic effects of long-term colchicine do not increase the risk of cancer, sepsis, cytopenia, or myotoxicity.

Modification of diet, exercise and lifestyle (MODEL) study: a randomised controlled trial protocol.

INTRODUCTION: Most cardiovascular disease (CVD)-related events could be prevented or substantially delayed with improved diet and lifestyle. Providing information on structural vascular disease may improve CVD risk factor management, but its impact on lifestyle change remains unclear. This study aims to determine whether providing visualisation and pictorial representation of structural vascular disease (abdominal aortic calcification (AAC)) can result in healthful diet and lifestyle change. METHODS AND ANALYSIS: This study, including men and women aged 60-80 years, is a 12-week, two-arm, multisite randomised controlled trial. At baseline, all participants will have AAC assessed from a lateral spine image captured using a bone densitometer. Participants will then be randomised to receive their AAC results at baseline (intervention group) or a usual care control group that will receive their results at 12 weeks. All participants will receive information about routinely assessed CVD risk factors and standardised (video) diet and lifestyle advice with three simple goals: (1) increase fruit and vegetable (FV) intake by at least one serve per day, (2) improve other aspects of the diet and (3) reduce sitting time and increase physical activity. Clinical assessments will be performed at baseline and 12 weeks. OUTCOMES: The primary outcome is a change in serum carotenoid concentrations as an objective measure of FV intake. The study design, procedures and treatment of data will adhere to Standard Protocol Items for Randomized Trials guidelines. ETHICS AND DISSEMINATION: Ethics approval for this study has been granted by the Edith Cowan University and the Deakin University Human Research Ethics Committees (Project Numbers: 20513 HODGSON and 2019-220, respectively). Results of this study will be published in peer-reviewed academic journals and presented in scientific meetings and conferences. Information regarding consent, confidentiality, access to data, ancillary and post-trial care and dissemination policy has been disclosed in the participant information form. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ACTRN12618001087246).

Implementation, mechanisms of impact and key contextual factors involved in outcomes of the Modification of Diet, Exercise and Lifestyle (MODEL) randomised controlled trial in Australian adults: protocol for a mixed-method process evaluation.

INTRODUCTION: The Modification of Diet, Exercise and Lifestyle (MODEL) study aims to examine the impact of providing visualisation and pictorial representation of advanced structural vascular disease (abdominal aortic calcification), on 'healthful' improvements to diet and lifestyle. This paper reports the protocol for the process evaluation for the MODEL study. METHODS AND ANALYSIS: The overall aim of the process evaluation is to understand the processes that took place during participation in the MODEL study trial and which elements were effective or ineffective for influencing 'healthful' behavioural change, and possible ways of improvement to inform wider implementation strategies. A mixed-method approach will be employed with the use of structured questionnaires and semistructured in-depth interviews. All 200 participants enrolled in the trial will undertake the quantitative component of the study and maximum variation sampling will be used to select a subsample for the qualitative component. The sample size for the qualitative component will be determined based on analytical saturation. Interviews will be digitally recorded and transcribed verbatim. Qualitative data will be analysed thematically and reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines. ETHICS AND DISSEMINATION: The MODEL study process evaluation has received approval from Edith Cowan University Human Research Ethics Committee (Project Number: 20513 HODGSON). Written informed consent will be obtained from all participants before they are included in the study. The study results will be shared with the individuals and institutions associated with this study as well as academic audiences through peer-reviewed publication and probable presentation at conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001087246.

Association Between Plasma Neutrophil Gelatinase-Associated Lipocalin and Cardiac Disease Hospitalizations and Deaths in Older Women.

Background Neutrophil gelatinase-associated lipocalin ( NGAL ) or lipocalin 2 may promote atherosclerosis and plaque instability leading to increased risk of cardiac events. We investigated the relationships between plasma NGAL , cardiovascular disease biomarkers, and long-term cardiac events. Methods and Results The study population consisted of 1131 ambulant older white women (mean age 75 years) without clinical coronary heart disease ( CHD ) and measures of plasma NGAL in the Perth Longitudinal Study of Ageing Women with 14.5-year CHD and heart failure hospitalizations or death (events) captured using linked records. Over 14.5 years, 256 women had CHD events, while 118 had heart failure events. Per SD increase in log-transformed NGAL there was a 35% to 37% increase in relative hazards for CHD and heart failure events in unadjusted analyses, which remained significant after adjustment for conventional risk factors for CHD events (hazard ratio 1.29, 95% CI 1.13-1.48, P<0.001) but not heart failure ( P>0.05). Women in the highest 2 quartiles of NGAL had higher relative hazards for CHD events compared with women in the lowest quartile hazard ratio 1.61, 95% CI 1.08-2.39, P=0.019 and hazard ratio 1.97, 95% CI 1.33-3.93, P=0.001, respectively. These associations were independent of high-sensitivity cardiac troponin I, homocysteine, and estimated renal function. NGAL correctly reclassified 1 in 4 women who sustained a CHD event up in risk and 1 in 10 women without CHD events down in risk. Conclusions NGAL was associated with increased risk of long-term CHD events, independent of conventional risk factors and biomarkers. These findings provide mechanistic insight into the role of NGAL with cardiac events.

Low-level cadmium exposure and cardiovascular outcomes in elderly Australian women: A cohort study.

BACKGROUND: Cadmium has been associated with increased risk of cardiovascular disease (CVD) in observational studies, however there has been a limited focus on this relationship in women. OBJECTIVES: This study investigated the association of urinary cadmium (UCd) concentrations with CVD outcomes and all-cause mortality in elderly Western Australian (WA) women. METHODS: UCd excretion was measured at baseline in 1359 women, mean age 75.2 ±â€¯2.7 years and 14.5 years of atherosclerotic vascular disease (ASVD) hospitalisations and deaths, including both the principle cause of death and all associated causes of death. Health outcome data were retrieved from the Western Australian Data Linkage System. Cox regression analysis was used to estimate hazard ratios of ASVD and all-cause mortality. UCd was ln-transformed and models were adjusted for demographic and CVD risk factors. RESULTS: Median (IQR) concentration of UCd was 0.18 (0.09-0.32) µg/L. In multivariable-adjusted analyses per ln unit (equivalent to ∼2.7 fold) increase in UCd, there was a 36% increase in the risk of death from heart failure and 17% increase in the risk of a heart failure event, respectively (HR = 1.36, 95% CI 1.11-1.67; HR = 1.17, 95% CI 1.01-1.35). When analyses were restricted to never smokers the relationship between UCd and death from heart failure remained (HR 1.29, 95% CI 1.01-1.63). CONCLUSIONS: This study suggests that even at low levels of exposure cadmium may be associated with heart failure hospitalisations and deaths in older women, however given the dilute nature of these urine samples, the results must be interpreted with caution.

Long-Term Effectiveness and Safety of Pravastatin in Patients With Coronary Heart Disease: Sixteen Years of Follow-Up of the LIPID Study.

BACKGROUND: We aimed to assess the long-term effects of treatment with statin therapy on all-cause mortality, cause-specific mortality, and cancer incidence from extended follow-up of the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial. METHODS AND RESULTS: LIPID initially compared pravastatin and placebo over 6 years in 9014 patients with previous coronary heart disease. After the double-blind period, all patients were offered open-label statin therapy. Data were obtained over a further 10 years from 7721 patients, by direct contact for 2 years, by questionnaires thereafter, and from mortality and cancer registries. During extended follow-up, 85% assigned pravastatin and 84% assigned placebo took statin therapy. Patients assigned pravastatin maintained a significantly lower risk of death from coronary heart disease (relative risk [RR] 0.89; 95% confidence interval [CI], 0.81-0.97; P=0.009), from cardiovascular disease (RR, 0.88; 95% CI, 0.81-0.95; P=0.002), and from any cause (RR, 0.91; 95% CI, 0.85-0.97; absolute risk reduction, 2.6%; P=0.003).Cancer incidence was similar by original treatment group during the double-blind period (RR, 0.94; 95% CI, 0.82-1.08; P=0.41), later follow-up (RR, 1.02; 95% CI, 0.91-1.14; P=0.74), and overall (RR, 0.99; 95% CI, 0.91-1.08; P=0.83). There were no significant differences in cancer mortality, or in the incidence of organ-specific cancers. Cancer findings were confirmed in a meta-analysis with other large statin trials with extended follow-up. CONCLUSIONS: In LIPID, the absolute survival benefit from 6 years of pravastatin treatment appeared to be maintained for the next 10 years, with a similar risk of death among survivors in both groups after the initial period. Treatment with statins does not influence cancer or death from noncardiovascular causes during long-term follow-up.

Abdominal Aortic Calcification Identified on Lateral Spine Images From Bone Densitometers Are a Marker of Generalized Atherosclerosis in Elderly Women.

OBJECTIVE: Dual-energy x-ray absorptiometry is a low-cost, minimal radiation technique used to improve fracture prediction. Dual-energy x-ray absorptiometry machines can also capture single-energy lateral spine images, and abdominal aortic calcification (AAC) is commonly seen on these images. APPROACH AND RESULTS: We investigated whether dual-energy x-ray absorptiometry-derived measures of AAC were related to an established test of generalized atherosclerosis in 892 elderly white women aged >70 years with images captured during bone density testing in 1998/1999 and B-mode carotid ultrasound in 2001. AAC scores were calculated using a validated 24-point scale into low (AAC24 score, 0 or 1), moderate (AAC24 scores, 2-5), and severe AAC (AAC24 scores, >5) seen in 45%, 36%, and 19%, respectively. AAC24 scores were correlated with mean and maximum common carotid artery intimal medial thickness (rs=0.12, P<0.001 and rs=0.14, P<0.001). Compared with individuals with low AAC, those with moderate or severe calcification were more likely to have carotid atherosclerotic plaque (adjusted prevalence ratio (PR), 1.35; 95% confidence interval, 1.14-1.61; P<0.001 and prevalence ratio, 1.94; 95% confidence interval, 1.65-2.32; P<0.001, respectively) and moderate carotid stenosis (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.39-3.54; P=0.001 and adjusted prevalence ratio, 4.82; 95% confidence interval, 3.09-7.050; P<0.001, respectively). The addition of AAC24 scores to traditional risk factors improved identification of women with carotid atherosclerosis as quantified by C-statistic (+0.075, P<0.001), net reclassification (0.249, P<0.001), and integrated discrimination (0.065, P<0.001). CONCLUSIONS: AAC identified on images from a dual-energy x-ray absorptiometry machine were strongly related to carotid ultrasound measures of atherosclerosis. This low-cost, minimal radiation technique used widely for osteoporosis screening is a promising marker of generalized extracoronary atherosclerosis.

Antithrombotic therapy in patients with combined coronary heart disease and atrial fibrillation.

Coronary heart disease (CHD) and atrial fibrillation (AF) commonly occur together. This presents challenges for the clinician treating patients with CHD, who require antiplatelet therapy and patients with AF, who require oral anticoagulant therapy. We have reviewed PubMed and SCOPUS to identify relevant guidelines, randomised clinical trials and registry studies and clinical trials presented at international meetings, and where necessary, clinical trial protocols to identify and critically analyze all relevant trials in which combinations of oral anticoagulants and antiplatelet agents in patients with AF and CHD have been evaluated. The available evidence on the efficacy and safety of combined oral anticoagulants and anti platelet agents was reviewed for the AF patient in three clinical scenarios: 1) after percutaneous coronary intervention (PCI); 2) after an acute coronary syndrome without PCI; and 3) in stable CHD. In each the clinical scenarios evaluated, there is limited clinical trial evidence to guide clinical management. Guidelines to help the clinician choose the right combinations of warfarin, clopidogrel and aspirin and the duration of treatment have been published, but they are based on a limited evidence base. There is even less evidence to guide the use of new oral anticoagulants (NOACs) in combination with the new P2Y12 antiplatelet agents. In each clinical scenario, the risks of coronary artery or stent thrombosis in CHD and risks of stroke in AF need to be carefully balanced against the risks of bleeding. We make recommendations for management based on the evidence which is available at this time and indicate the many gaps which are currently being addressed by randomized clinical trials.

Biomarkers in stable coronary heart disease, their modulation and cardiovascular risk: The LIPID biomarker study.

AIMS: In patients with stable coronary heart disease (CHD), we aimed to assess 1. the prognostic power of biomarkers reflecting haemodynamics, micronecrosis, inflammation, coagulation, lipids, neurohumoral activity, and renal function; 2. whether changes in concentrations of these biomarkers over 12 months affected subsequent CHD risk; and 3. whether pravastatin modified the change in biomarker concentrations and this influenced the risk of future events. METHODS: In the LIPID study, 9014 patients were randomised to pravastatin 40 mg or placebo 3-36 months after an acute coronary syndrome. Eight biomarkers were measured at baseline (n=7863) and 12 months later (n=6434). RESULTS: During a median of 6.0 (IQR 5.5-6.5) years follow-up, 1100 CHD-related deaths and nonfatal myocardial infarctions occurred, 694 after biomarker measurement at 12 months. Baseline BNP, CRP, cystatin C, D-dimer, midregional pro-adrenomedullin, and sensitive troponin I predicted recurrent CHD events. In a multivariable model, sensitive troponin I, BNP, and cystatin C had the strongest associations with outcome (P<0.001 for trend). The strongest improvement in risk prediction was achieved by including sensitive troponin I (net reclassification improvement (NRI) 5.5%; P=0.003), BNP (4.3%; P=0.02), history of MI (NRI 7.0%; P<0.001). In landmark analyses, among biomarkers, changes to 12 months in sensitive troponin I (HR 1.32 (1.03-1.70) for T3/T1), BNP (HR 1.37 (1.10-1.69) for Q4/Q1) and Lp-PLA2 (HR 1.52 (1.16-1.97)) improved CHD risk prediction. CONCLUSIONS: Baseline levels and changes in sensitive troponin I, and BNP may have the potential to guide the intensity of secondary prevention therapy.

Optimising pharmacotherapy for secondary prevention of non-invasively managed acute coronary syndrome.

About half of all patients who experience an acute coronary syndrome (ACS) in Australia have their conditions managed non-invasively - that is, they do not undergo coronary angiography and revascularisation in hospital. ACS patients whose conditions are managed non-invasively may not receive the same level of evidence-based care as those who receive coronary revascularisation. This article reviews the optimal pharmacological management of ACS managed non-invasively. There is strong evidence to support the prescription of dual antiplatelet therapy (DAPT; aspirin with a P2Y12 inhibitor). DAPT should continue for 12 months after an ACS, then aspirin should be continued indefinitely. Anticoagulation with warfarin or a novel oral anticoagulant may be needed if atrial fibrillation occurs; the combination with DAPT increases the risk of bleeding. Unless contraindicated, high-intensity statin therapy should be prescribed for all post-ACS patients irrespective of their cholesterol level. Non-statin lipid therapy has not been shown to improve outcomes. Use of ß-adrenergic blockers is recommended in most guidelines, but the clinical trials to support this recommendation were performed more than 30 years ago, and routine long-term use may not be relevant to modern treatment, except when there is cardiac failure or left ventricular dysfunction. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are also widely recommended, but the evidence for benefit is stronger when there is left ventricular dysfunction. Calcium-channel blockers, nitrates, antiarrhythmic drugs, digoxin and diuretics do not improve outcomes in post-ACS patients.

Eight challenges faced by general practitioners caring for patients after an acute coronary syndrome.

The general practitioner is essential in the management of the patient who has recently been discharged from hospital following an acute coronary syndrome (ACS), particularly as duration of hospital stay is shorter than in previous decades. GPs caring for patients after an ACS face numerous challenges. Often, the first of these is insufficient or delayed documentation from the discharging hospital, although electronic discharge summaries are alleviating this problem. Post-ACS patients often have comorbidities, and GPs play a key role in managing these. Patients taking dual antiplatelet therapy who need surgery, and post-ACS patients with atrial fibrillation, require particular care from GPs. Patients will often approach their GP for advice on the safety of other drugs, such as smoking cessation medication, and phosphodiesterase type 5 inhibitors for erectile dysfunction. For patients complaining of persistent lethargy after an ACS, GPs must consider several differential diagnoses, including depression, hypotension, hypovolaemia, and side effects of ß-blockers. GPs play an important ongoing role in ensuring that target cholesterol levels are reached with statin therapy; this includes ensuring long-term adherence. They may also need to advise patients who want to stop statin therapy, usually due to perceived side effects. Many of these challenges can be met with improved and respectful communication between the hospital, the treating cardiologist and the GP. The patient needs to be closely involved in the decision-making process, particularly when balancing the risks of bleeding versus thrombosis.

Management of acute coronary syndrome in special subgroups: female, older, diabetic and Indigenous patients.

While the evidence base for management of acute coronary syndrome (ACS) is extensive, some subgroups have been underrepresented or excluded from relevant clinical trials. These subgroups - such as women, older people, diabetic patients and Indigenous Australians - present clinical challenges for which there is limited evidence to guide optimal therapy. Women may have a different pattern of presentation, with potential for delays in diagnosis and worse outcomes in ST-elevation myocardial infarction, but there is no evidence that treatments affect them differently from men. Older people suffer from a high-risk, low-treatment paradox. This may be due to under-appreciation of the benefits of treatments for older people, or to good clinical judgement in avoiding harm from worsening age-related comorbidities. Patients with diabetes have a high risk of ACS and suffer worse outcomes. Moderate glycaemic control with close monitoring and avoidance of hypoglycaemia are recommended. Coronary artery bypass grafting is preferred to percutaneous coronary intervention for patients with diabetes and multivessel disease, although the latter is reasonable in single-vessel disease. Indigenous patients have a high prevalence of coronary disease, with more frequent coronary events at a young age, a heavy load of risk factors and poor outcomes after ACS. The complex sociocultural barriers to treatment are yet to be addressed adequately.

Managing antithrombotic therapy in patients with both atrial fibrillation and coronary heart disease.

PURPOSE: Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy. METHODS: We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents. FINDINGS: Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y12 inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events. IMPLICATIONS: Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y12 inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care.

Comparison of estimated glomerular filtration rate by the chronic kidney disease epidemiology collaboration (CKD-EPI) equations with and without Cystatin C for predicting clinical outcomes in elderly women.

BACKGROUND: Reduced estimated glomerular filtration rate (eGFR) using the cystatin-C derived equations might be a better predictor of cardiovascular disease (CVD) mortality compared with the creatinine-derived equations, but this association remains unclear in elderly individuals. AIM: The aims of this study were to compare the predictive values of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C eGFR equations for all-cause mortality and CVD events (hospitalizations±mortality). METHODS: Prospective cohort study of 1165 elderly women aged>70 years. Associations between eGFR and outcomes were examined using Cox regression analysis. Test accuracy of eGFR equations for predicting outcomes was examined using Receiver Operating Characteristic (ROC) analysis and net reclassification improvement (NRI). RESULTS: Risk of all-cause mortality for every incremental reduction in eGFR determined using CKD-EPI-creatinine, CKD-EPI-cystatin C and the CKD-EPI-creatinine-cystatic C equations was similar. Areas under the ROC curves of CKD-EPI-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C equations for all-cause mortality were 0.604 (95%CI 0.561-0.647), 0.606 (95%CI 0.563-0.649; p = 0.963) and 0.606 (95%CI 0.563-0.649; p = 0.894) respectively. For all-cause mortality, there was no improvement in the reclassification of eGFR categories using the CKD-EPI-cystatin C (NRI -4.1%; p = 0.401) and CKD-EPI-creatinine-cystatin C (NRI -1.2%; p = 0.748) compared with CKD-EPI-creatinine equation. Similar findings were observed for CVD events. CONCLUSION: eGFR derived from CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C equations did not improve the accuracy or predictive ability for clinical events compared to CKD-EPI-creatinine equation in this cohort of elderly women.

Cardiovascular disease risk score prediction models for women and its applicability to Asians.

PURPOSE: Although elevated cardiovascular disease (CVD) risk factors are associated with a higher risk of developing heart conditions across all ethnic groups, variations exist between groups in the distribution and association of risk factors, and also risk levels. This study assessed the 10-year predicted risk in a multiethnic cohort of women and compared the differences in risk between Asian and Caucasian women. METHODS: Information on demographics, medical conditions and treatment, smoking behavior, dietary behavior, and exercise patterns were collected. Physical measurements were also taken. The 10-year risk was calculated using the Framingham model, SCORE (Systematic COronary Risk Evaluation) risk chart for low risk and high risk regions, the general CVD, and simplified general CVD risk score models in 4,354 females aged 20-69 years with no heart disease, diabetes, or stroke at baseline from the third Australian Risk Factor Prevalence Study. Country of birth was used as a surrogate for ethnicity. Nonparametric statistics were used to compare risk levels between ethnic groups. RESULTS: Asian women generally had lower risk of CVD when compared to Caucasian women. The 10-year predicted risk was, however, similar between Asian and Australian women, for some models. These findings were consistent with Australian CVD prevalence. CONCLUSION: In summary, ethnicity needs to be incorporated into CVD risk assessment. Australian standards used to quantify risk and treat women could be applied to Asians in the interim. The SCORE risk chart for low-risk regions and Framingham risk score model for incidence are recommended. The inclusion of other relevant risk variables such as obesity, poor diet/nutrition, and low levels of physical activity may improve risk estimation.

Targeting cholesterol crystal-induced inflammation for the secondary prevention of cardiovascular disease.

Cholesterol crystals are present in nascent and advanced atherosclerotic plaque. Under some conditions, they may enlarge and cause direct plaque trauma or trigger an inflammatory cascade that promotes the growth and instability of atherosclerotic plaque. Therapies that reduce the risk of cholesterol crystal formation or prevent the associated inflammatory response have the potential to improve the clinical outcome of patients with cardiovascular disease. Statins have pleiotropic effects that can reduce the size of the free cholesterol pool contained within atherosclerotic plaques and prevent the formation of cholesterol crystals. Colchicine prevents crystal-induced inflammation by virtue of its ability to inhibit macrophage and neutrophil function. Both statins and colchicine have been demonstrated to reduce the risk of cardiovascular events in patients with stable coronary disease. The efficacy of statins and colchicine for cardiovascular prevention supports the hypothesis that crystal-induced inflammation plays an integral role in the progression and instability of coronary disease. Inhibition of cholesterol crystal-induced inflammation offers a promising new target for the secondary prevention of cardiovascular disease.

The use of coronary revascularisation procedures in urban Australian Aboriginals and a matched general population coronary procedures in Aboriginals.

BACKGROUND: Coronary revascularisation procedures may be under-used for Aboriginal Australians with ischaemic heart disease (IHD). We compared the use of procedures in an urban Aboriginal population and a non-Aboriginal external comparison group. METHODS: The Perth Aboriginal Atherosclerosis Risk (PAARS) cohort (n=998) and 3695 age- and sex-matched non-Aboriginals were electronically linked to Western Australian hospital morbidity data to identify admissions and revascularisation procedures between 1980 and 2006. RESULTS: There were 731 admissions for IHD for 983 PAARS participants with hospital admissions and 391 in 3150 non-Aboriginals. There were 136 first procedures overall; 43% of Aboriginals having a procedure were women versus 18.5% of non-Aboriginals. 41% of Aboriginal patients and 48% of non-Aboriginals had procedures (p=0.12). Aboriginals were more likely to have coronary artery bypass grafts (CABG) (40.5%) than a percutaneous coronary intervention (PCI), compared to the general population (23%, p=0.02). The proportion of first procedures for acute coronary syndrome (ACS) admissions was 61% for both groups, 80% and 85%, respectively, being PCI. CONCLUSIONS: Coronary revascularisation procedures for IHD were used with equal frequency in Aboriginal people and matched non-Aboriginals. Aboriginal people were more likely to have CABG than PCI. Revascularisation rate and type in ACS admissions were the same.

Coronary heart disease events in Aboriginal Australians: incidence in an urban population.

OBJECTIVE: To determine the incidence of coronary heart disease (CHD) events in an urban Aboriginal population. DESIGN, SETTING AND PARTICIPANTS: Cohort study of 906 Aboriginal people without CHD from 998 who had undergone risk-factor assessment in the Perth Aboriginal Atherosclerosis Risk Study (PAARS) in 1998-1999. PAARS cohort data were electronically linked to a range of databases that included Western Australian hospital morbidity data and death registry data. We analysed data from January 1980 to December 2006 to identify previous admissions for CHD from 1980 to baseline (1998-1999) and new events from baseline to 2006. MAIN OUTCOME MEASURE: First CHD event (hospital admission or death). RESULTS: There were 891 linked records for the 906 participants without previous CHD. The event rate was 12.6/1000 person-years (95% CI, 10.2-15.6/1000 person-years). Annual CHD event rates ranged from 8 to 18/1000 person-years. After adjustment for age (sex was not associated with the risk factors assessed), factors associated with risk of a CHD event in the PAARS cohort were a history of diabetes, overweight or obesity (indicated by body mass index), smoking, and hypertension, but not waist circumference. People with these risk factors were 1.9-2.7 times more likely to experience a CHD event. Compared with previously published information from a remote Aboriginal community in the Northern Territory, the incidence of CHD events among urban-dwelling Aboriginal people was not significantly different (P > 0.05 overall and for subgroups defined by age and sex). CONCLUSIONS: City-dwelling Aboriginal Australians have an incidence of CHD events comparable to that of Aboriginal people living in remote northern Australia.