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Background Heart failure (HF) remains a common complication for patients with coronary artery disease (CAD), especially after acute myocardial infarction. Although left ventricular ejection fraction (LVEF) is conventionally used to assess cardiac function for risk stratification, it has been shown in other settings to underestimate the risk of HF compared with global longitudinal strain (GLS). Moreover, most evidence pertains to early-onset HF. We sought the clinical and myocardial predictors for late-onset HF in patients with CAD. Methods We analyzed echocardiograms (including GLS) in 334 patients with CAD (ages 65 ± 11 years, 77% male) who were enrolled in the Nurse-Led Intervention for Less Chronic Heart Failure trial, a prospective, randomized controlled trial that compared standard care with nurse-led intervention to prevent HF in individuals at risk of incident HF. Long-term (9 years) follow-up was obtained via data linkage. Analysis was performed using a competing-risk model. Results Baseline LVEF values were normal or mildly impaired (LVEF ≥ 40%) in all subjects. After a median of 9 years of follow-up, 50 (15%) of the 334 patients had new HF admissions, and 68 (20%) died. In a competing-risk model, HF was associated with GLS (hazard ratio = 1.15 [1.05-1.25], P = .001), independent of estimated glomerular filtration rate (hazard ratio = 0.98 [0.97-0.99], P = .045), Charlson comorbidity score (hazard ratio = 1.64 [1.25-2.15], P < .001), or E/e’ (hazard ratio = 1.08 [1.02-1.14], P = .01). Global longitudinal strain—but not conventional echocardiographic measures—added incremental value to a clinical model based on age, gender, and Charlson score (area under the curve, 0.78-0.83, P = .01). Global longitudinal strain was still associated with HF development in patients taking baseline angiotensin convertase enzyme inhibitors (hazard ratio = 1.21 [1.11-1.31], P < .01) and baseline beta-blockers (1.17 [1.09, 1.26]; P < .01). Mortality was associated with older men, risk factors (hypertension or diabetes), and comorbidities (AF and chronic kidney disease). Conclusions Global longitudinal strain is independently associated with risk of incident HF in patients admitted with CAD and provides incremental prognostic value to standard markers. Identifying an at-risk subgroup using GLS may be the focus of future randomized controlled trails to enable targeted therapeutic intervention.

Aims To examine sex-stratified differences in the association of left ventricular ejection fraction-based heart failure (HF) subtypes and the characteristics and correlates of self-reported changes in HF symptoms. Methods and results We report a secondary data analysis from 528 hospitalized individuals diagnosed with HF characterised by a reduced, mildly reduced, or preserved ejection fraction [HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), or HF with preserved ejection fraction (HFpEF)] who completed 12-month follow-up within a multicentre disease management trial. There were 302 men (71.1 ± 11.9 years, 58% with HFrEF) and 226 women (77.1 ± 10.6 years, 49% with HFpEF). The characteristics of self-reported symptoms measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12-month were analysed. At baseline, shortness of breath and fatigue predominated; with key differences according to HF subtypes in bilateral ankle oedema (both sexes), walking problems (women) and depressive symptoms (men). At 12-month follow-up, most KCCQ scores had not significantly changed. However, 25% of individuals reported worse symptom. In women, those with HFpEF had worse symptoms than those with HFmrEF/HFrEF (P = 0.025). On an adjusted basis, women [odds ratios (OR): 1.78, 95% confidence interval (CI): 1.00–3.16 vs. men], those with coronary artery disease (OR: 2.01, 95% CI: 1.21–3.31) and baseline acute pulmonary oedema (OR: 1.67, 95% CI: 1.02–2.75) were most likely to report worsening symptoms. Among men, worsening symptoms correlated with a history of hypertension (OR: 2.16, 95% CI: 1.07–4.35) and a non-English-speaking background (OR: 2.30, 95% CI: 1.02–5.20). Conclusion We found significant heterogeneity (with potential clinical implications) in the symptomatic characteristics and subsequent symptom trajectory according to the sex and HF subtype of those hospitalized with the syndrome. Trial Registration ANZCTR12613000921785

Aims We investigated long-term mortality associated with changes in left ventricular ejection fraction (LVEF) in a large, real-world patient cohort. Methods and results A total of 117 275 adults (63 ± 16 years, 46% women) had LVEF quantified by the same method ≥6 months apart. This included 17 343 cases (66 ± 15 years, 48% women) being initially investigated for heart failure (HF). During 3.3 [interquartile range (IQR) 1.7–6.0] years from first to last echocardiogram, median change in LVEF was −1 (IQR −8 to +5) units from a baseline of 62% (IQR 54–69%). During subsequent 7.6 (IQR 4.3–10.1) years of follow-up, 11 397 (9.7%) and 34 101 (29.1%) cases died from cardiovascular disease and all causes, respectively. Actual 5-year, all-cause mortality increased from 12% to 29% among those with the smallest to the largest decrease in LVEF (from 30 units); the adjusted risk of cardiovascular-related mortality increased two- to eightfold beyond a >10-unit decline in LVEF (vs. minimal change; P 30-unit increase to >30-unit decline in LVEF (vs. minimal change; P

Aortic stenosis is the most common cardiac valve disorder requiring clinical management. However, there is little evidence on the societal cost of progressive aortic stenosis. We sought to quantify the societal burden of premature mortality associated with progressively worse aortic stenosis.In this observational clinical cohort study, we examined echocardiograms on native aortic valves of 98 565 men and 99 357 women aged 65 years or older across 23 sites in Australia, from Jan 1, 2003, to Dec 31, 2017. Individuals were grouped according to their peak aortic valve velocity in 0·50 m/s increments up to 4·00 m/s or more (severe aortic stenosis), using 1·00-1·99 m/s (no aortic stenosis) as the reference group. Sex-specific premature mortality and years of life lost during a 5-year follow-up were calculated, along with willingness-to-pay to regain quality-adjusted life years (QALYs).Overall, 20 701 (21·0%) men and 18 576 (18·7%) women had evidence of mild-to-severe aortic stenosis. The actual 5-year mortality in men with normal aortic valves was 32·1% and in women was 26·1%, increasing to 40·9% (mild aortic stenosis) and 52·2% (severe aortic stenosis) in men and to 35·9% (mild aortic stenosis) and 55·3% (severe aortic stenosis) in women. Overall, the estimated societal cost of premature mortality associated with aortic stenosis was AU$629 million in men and $735 million in women. Per 1000 men and women investigated, aortic stenosis was associated with eight more premature deaths in men resulting in 32·5 more QALYs lost (societal cost of $1·40 million) and 12 more premature deaths in women resulting in 57·5 more QALYs lost (societal cost of $2·48 million) when compared with those without aortic stenosis.Any degree of aortic stenosis in older individuals is associated with premature mortality and QALYs. In this context, there is a crucial need for cost-effective strategies to promptly detect and optimally manage this common condition within our ageing populations.Edwards LifeSciences, National Health and Medical Research Council of Australia, and the National Heart, Lung, and Blood Institute.

Background Although mild pulmonary hypertension is known to be associated with increased mortality, its impact on premature mortality is largely unknown. Methods We studied the distribution of estimated right ventricular systolic pressure (eRVSP) among a total of 154 956 adults with no evidence of left heart disease investigated with echocardiography. We then examined individually linked mortality, premature mortality and associated life-years lost (LYL) according to eRVSP levels. Results The cohort comprised 70 826 men and 84 130 women (aged 61.3±17.7 and 61.4±18.4 years, respectively). Overall, 85 173 (55.0%), 49 276 (31.8%), 13 060 (8.4%) and 7447 (4.8%) cases had eRVSP levels indicative of no (

Aims We extended follow-up of a heart failure (HF) prevention study to determine if initially positive findings of improved cardiac recovery were translated into less de novo HF and/or all-cause mortality (primary endpoint) in the longer term. Methods and results The Nurse-led Intervention for Less Chronic HF (NIL-CHF) study was a single-centre randomized trial of nurse-led prevention involving cardiac inpatients without HF. At 3 years, 454 survivors (aged 66 ± 11 years, 71% men and 68% coronary artery disease) had the following: (i) a normal echocardiogram (128 cases/28.2%), (ii) structural heart disease (196/43.2%), or (iii) left ventricular diastolic dysfunction/left ventricular systolic dysfunction (LVDD/LVSD: 130/28.6%). Outcomes were examined during median 8.3 (interquartile range 7.8–8.8) years according to these hierarchal groups and change in cardiac status from baseline to 3 years. Overall, 109 (24.0%) participants had a de novo HF admission or died while accumulating 551 cardiovascular-related admissions/3643 days of hospital stay. Progressively worse cardiac status correlated with increased hospitalizations (P < 0.001). The mean rate (95% confidence interval) of cardiovascular admissions/days of hospital stay being 0.09 (0.05–0.12) admissions/0.33 (0.13–0.54) days vs. 0.27 (0.20–0.34) admissions/2.20 (1.36–3.04) days per annum for those with a normal echocardiogram vs. LVDD/LVSD at 3 years. With progressively higher event rates, the adjusted hazard ratio for a de novo HF admission and/or death associated with a structural abnormality (24.5% of cases) and LVDD/LVSD (36.2%) at 3 years was 1.57 (0.82–3.01; P = 0.173) and 2.07 (1.05–4.05; P = 0.035) compared with a normal echocardiogram (10.9%). Mortality also mirrored the direction/extent of cardiac status/trajectory. Conclusions These data suggest the positive initial effects of NIL-CHF intervention on cardiac recovery contributed to better long-term outcomes among patients at high risk of HF. However, prevention of HF remains challenging.

Objectives This study aimed to determine the association of stage B heart failure (SBHF) and its constituent left ventricular (LV) abnormalities with trajectory of exercise capacity over time, and assess whether this association is modified by reversion of these LV abnormalities to normal. Background The LV abnormalities of SBHF may coincide with a reduction in exercise capacity that precedes the overt exercise intolerance of clinical heart failure (HF). Determining the predictive capacity of established and novel SBHF criteria for exercise capacity decline may improve HF risk stratification. Methods LV structure/function (echocardiography) and exercise capacity (6-min walk distance [6MWD]) were assessed at baseline and 3-year follow-up in 268 patients from the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (all stage A [SAHF] or SBHF). Changes (Δ) in 6MWD were compared between SAHF and SBHF and across each of 4 constituent components of SBHF: LV hypertrophy, regional wall motion abnormality(ies) (RWMA), left ventricular systolic dysfunction (LVSD) (ejection fraction Results Δ6MWD was similar in those with SAHF (n = 141) and SBHF (n = 127; −5 m [95% confidence interval (CI): −21 to +11 m]; covariate-adjusted). However, within the setting of SBHF there was substantive heterogeneity; that is, reductions in 6MWD were observed with persistent elevated E/e’ (−34 m [95% CI: −62 to −6 m]) and persistent LVSD (−41 m [95% CI: −74 to −8 m]), but not with LV hypertrophy (+17 m [95% CI: −15 to +49 m) or RWMA (+5 m [−27 to +36 m]), nor in patients whose elevated E/e’ or LVSD reverted to normal by 3 years (p > 0.10). Conclusions Elevated E/e’ is associated with a similar degree of exercise capacity decline to LVSD, supporting that both LV functional criteria be considered in distinguishing SBHF from SAHF. That reversion of either manifestation of LV dysfunction was associated with preserved exercise capacity advocates targeting of these factors by HF preventive interventions.

Background: To examine mild cognitive impairment and its associations with subclinical cardiac dysfunction in patients with chronic heart disease yet to develop the clinical syndrome of chronic heart failure (CHF). Methods and results: Patients from the Nurse-led Intervention for Less Chronic Heart Failure Study (n = 373 with chronic heart disease other than CHF; 64 ± 11 years, 69% men) were screened for mild cognitive impairment [Montreal cognitive assessment (MoCA) score < 26] and underwent echocardiographic/clinical profiling. We investigated associations of mild cognitive impairment and MoCA cognitive domain subscores with global cardiac status (‘normal’ vs. ‘diastolic dysfunction’ vs. ‘other cardiac abnormality’) and individual echocardiographic parameters. Patients with mild cognitive impairment (n = 161; 43%) demonstrated a higher age-adjusted prevalence of diastolic dysfunction (37% vs. 24%; P < 0.05). Multivariate logistic regression (adjusted for age, sex, and other relevant clinical factors) indicated that the odds of mild cognitive impairment were two-times higher with diastolic dysfunction (P = 0.030) and 1.7-times higher with ‘other cardiac abnormalities’ (P = 0.082) vs. normal cardiac status. In turn, mild cognitive impairment was predicted by left-ventricular (LV) filling pressure (based on the ratio of early diastolic filling and annular velocities; adjusted odds ratio 1.07 per unit increase, P = 0.022), but not LV structural parameters. Specific deficits in the cognitive domains of executive functioning and visuo-constructional abilities were also independently predicted by diastolic dysfunction (P < 0.05). Conclusion: Mild cognitive impairment is prevalent in patients with subclinical chronic heart disease at high-risk of CHF. Independent associations with LV diastolic dysfunction suggest a link between cardiac and cognitive functioning beyond shared risk factors.

Background: The potential impact of disease management to optimize quality of care, health outcomes, and total healthcare costs across a range of cardiac disease states is unknown. Methods: A trial-based cost-utility analysis was conducted alongside a randomized controlled trial of 335 patients with chronic, non-valvular AF (without heart failure; the SAFETY Trial) discharged to home from three tertiary referral hospitals in Australia. A home-based disease management intervention (the SAFETY intervention) that involved community-based AF care including home visits was compared to routine primary healthcare and hospital outpatient follow-up (standard management). Bootstrapped incremental cost-utility ratios were computed based on quality-adjusted life-years (QALYs) and total healthcare costs. Cost-effectiveness acceptability curves were constructed to explore the probability of the SAFETY intervention being cost-effective. Sub-group analyses were performed based on age and sex to determine differential cost-effectiveness. Results: During median follow-up of 1.75 years, the SAFETY intervention was associated with a non-statistically significant increase in QALYs (0.02 per person) and lower total healthcare costs (–$4,375 per person). Although each of these findings were not statistically significant, the SAFETY intervention was found to be dominant (more effective and cost saving) in 58.8% of the bootstrapped iterations and cost-effective (more effective and gains in QALYs achieved at or below $50,000 per QALY gained) in 61.5% of the iterations. Males and those aged less than 78 years achieved greater gains in QALYs and savings in healthcare costs. The estimated value of perfect information in Australia (the monetized value of removing uncertainty in the cost-effectiveness results) was A$51 million, thus demonstrating the high potential gain from further research. Conclusions: Compared with standard management, the SAFETY intervention is potentially a dominant strategy for those with chronic, non-valvular AF. However, there would be substantial value in reducing the uncertainty in these estimates from further research. Trial registration:Australian New Zealand Clinical Trials Registry identifier: ACTRN12610000221055.

BackgroundThere is a paucity of primary data to understand the overall pattern of disease and injuries as well as related health-service utilization in resource-poor countries in Africa.ObjectiveTo generate reliable and robust data describing the pattern of emergency presentations attributable to communicable disease (CD), non-communicable disease (NCD) and injuries in three different regions of Mozambique.MethodsWe undertook a pragmatic, prospective, multicentre surveillance study of individuals (all ages) presenting to the emergency departments of three hospitals in Southern (Maputo), Central (Beira) and Northern (Nampula) Mozambique. During 24-hour surveillance in the seasonally distinct months of April and October 2016/2017, we recorded data on 7,809 participants randomly selected from 39,124 emergency presentations to the three participating hospitals. Applying a pragmatic surveillance protocol, data were prospectively collected on the demography, clinical history, medical profile and treatment of study participants.FindingsA total of 4,021 males and 3,788 (48.5%) females comprising 630 infants (8.1%), 2,070 children (26.5%), 1,009 adolescents (12.9%) and, 4,100 adults (52.5%) were studied. CD was the most common presentation (3,914 cases/50.1%) followed by NCD (1,963/25.1%) and injuries (1,932/24.7%). On an adjusted basis, CD was more prevalent in younger individuals (17.9±17.7 versus 26.6±19.2 years;pInterpretationApplying highly pragmatic surveillance methods suited to the low-resource setting of Mozambique, these unique data provide critical insights into the differential pattern of CD, NCD and injury. Consequently, they highlight specific health priorities across different regions and seasons in Southern Africa.

Background The impact of different patterns of multimorbidity in heart failure (HF) on health outcomes is unknown. Objectives The aim of this study was to test the hypothesis that, independent of the extent of comorbidity, there are distinctive phenotypes of multimorbidity that convey an increased risk for premature mortality in patients hospitalized with HF. Methods We analyzed the clinical profile and health outcomes of 787 patients hospitalized with HF participating in a multidisciplinary HF management program with a minimum 12-month follow-up. A Classification and Regression Tree model was applied to explore the distinctive combinations of 10 most prevalent concurrent conditions (other than coronary artery disease and hypertension) associated with 12-month all-cause mortality. Results Mean (SD) age was 74 (12) years (59% men), and 65% had left ventricular systolic dysfunction. Most patients (88%) had 3 or more comorbid conditions, with a mean of 4.3 concurrent conditions in addition to HF. A total of 248 patients (32%) died (median, 663 [IQR, 492-910] days), including 142 deaths (18%) within 12 months. Patients with concurrent dysrhythmia, anemia, and respiratory disease experienced significantly higher 12-month all-cause mortality than those without these conditions (36.1% vs 3.6%, respectively; hazard ratio, 6.1 [95% confidence interval, 2.0-19.1]). Overall, this "malignant" phenotype of multimorbidity was associated with not only a markedly increased risk of all-cause mortality but also more unplanned readmissions, longer inpatient stays, and highest costs in the short (30-day) and longer terms when compared with more "benign" phenotypes of multimorbidity. Conclusions We found a differential pattern of health outcomes according to pattern of comorbidity present in older patients hospitalized with HF and exposed to postdischarge, multidisciplinary management.

Background— We sought to determine the overall impact of a nurse-led, multidisciplinary home-based intervention (HBI) adapted to hospitalized patients with chronic forms of heart disease of varying types. Methods and Results— Prospectively planned, combined, secondary analysis of 3 randomized trials (1226 patients) of HBI were compared with standard management. Hospitalized patients presenting with heart disease but not heart failure, atrial fibrillation but not heart failure, and heart failure, as well, were recruited. Overall, 612 and 614 patients, respectively, were allocated to a home visit 7 to 14 days postdischarge by a cardiac nurse with follow-up and multidisciplinary support according to clinical need or standard management. The primary outcome of days-alive and out-of-hospital was examined on an intention-to-treat basis. During 1371 days (interquartile range, 1112–1605) of follow-up, 218 patients died and 17 917 days of hospital stay were recorded. In comparison with standard management, HBI patients achieved significantly prolonged event-free survival (90.1% [95% confidence interval, 88.2–92.0] versus 87.2% [95% confidence interval, 85.1–89.3] days-alive and out-of-hospital; P =0.020). This reflected less all-cause mortality (adjusted hazard ratio, 0.67; 95% confidence interval, 0.50–0.88; P =0.005) and unplanned hospital stay (median, 0.22 [interquartile range, 0–1.3] versus 0.36 [0–2.1] days/100 days follow-up; P =0.011). Analyses of the differential impact of HBI on all-cause mortality showed significant interactions (characterized by U-shaped relationships) with age ( P =0.005) and comorbidity ( P =0.041); HBI was most effective for those aged 60 to 82 years (59%–65% of individual trial cohorts) and with a Charlson Comorbidity Index Score of 5 to 8 (36%–61%). Conclusions— These data provide further support for the application of postdischarge HBI across the full spectrum of patients being hospitalized for chronic forms of heart disease. Clinical Trial Registration— URL: http://www.anzctr.org.au . Unique identifiers: 12610000221055, 12608000022369, 12607000069459.

To assess the long-term cost-effectiveness of two multidisciplinary management programs for elderly patients hospitalized with chronic heart failure (CHF) and how it is influenced by patient characteristics.A trial-based analysis was conducted alongside a randomized controlled trial of 280 elderly patients with CHF discharged to home from three Australian tertiary hospitals. Two interventions were compared: home-based intervention (HBI) that involved home visiting with community-based care versus specialized clinic-based intervention (CBI). Bootstrapped incremental cost-utility ratios were computed based on quality-adjusted life-years (QALYs) and total healthcare costs. Cost-effectiveness acceptability curves were constructed based on incremental net monetary benefit (NMB). We performed multiple linear regression to explore which patient characteristics may impact patient-level NMB.During median follow-up of 3.2 years, HBI was associated with slightly higher QALYs (+0.26 years per person; p=0.078) and lower total healthcare costs (AU$ -13,100 per person; p=0.025) mainly driven by significantly reduced duration of all-cause hospital stay (-10 days; p=0.006). At a willingness-to-pay threshold of AU$ 50,000 per additional QALY, the probability of HBI being better-valued was 96% and the incremental NMB of HBI was AU$ 24,342 (discounted, 5%). The variables associated with increased NMB were HBI (vs. CBI), lower Charlson Comorbidity Index, no hyponatremia, fewer months of HF, fewer prior HF admissions1 year and a higher patient's self-care confidence. HBI's net benefit further increased in those with fewer comorbidities, a lower self-care confidence or no hyponatremia.Compared with CBI, HBI is likely to be cost-effective in elderly CHF patients with significant comorbidity.

IntroductionNumerous studies have found associations between characteristics of urban environments and risk factors for dementia and cognitive decline, such as physical inactivity and obesity. However, the contribution of urban environments to brain and cognitive health has been seldom examined directly. This cohort study investigates the extent to which and how a wide range of characteristics of urban environments influence brain and cognitive health via lifestyle behaviours in mid-aged and older adults in three cities across three continents.Methods and analysisParticipants aged 50–79 years and living in preselected areas stratified by walkability, air pollution and socioeconomic status are being recruited in Melbourne (Australia), Barcelona (Spain) and Hong Kong (China) (n=1800 total; 600 per site). Two assessments taken 24 months apart will capture changes in brain and cognitive health. Cognitive function is gauged with a battery of eight standardised tests. Brain health is assessed using MRI scans in a subset of participants. Information on participants’ visited locations is collected via an interactive web-based mapping application and smartphone geolocation data. Environmental characteristics of visited locations, including the built and natural environments and their by-products (e.g., air pollution), are assessed using geographical information systems, online environmental audits and self-reports. Data on travel and lifestyle behaviours (e.g., physical and social activities) and participants’ characteristics (e.g., sociodemographics) are collected using objective and/or self-report measures.Ethics and disseminationThe study has been approved by the Human Research Ethics Committee of the Australian Catholic University, the Institutional Review Board of the University of Hong Kong and the Parc de Salut Mar Clinical Research Ethics Committee of the Government of Catalonia. Results will be communicated through standard scientific channels. Methods will be made freely available via a study-dedicated website.Trial registration numberACTRN12619000817145.

Background Peaks and troughs in cardiovascular events correlated with seasonal change is well established from an epidemiological perspective but not a clinical one. Methods Retrospective analysis of the recruitment, baseline characteristics and outcomes during minimum 12-month exposure to all four seasons in 1598 disease-management trial patients hospitalised with chronic heart disease. Seasonality was prospectively defined as ≥4 hospitalisations (all-cause) AND >45% of related bed-days occurring in any one season during median 988 (IQR 653, 1394) days follow-up. Results Patients (39% female) were aged 70 ± 12 years and had a combination of coronary artery disease (58%), heart failure (54%), atrial fibrillation (50%) and multimorbidity. Overall, 29.9% of patients displayed a pattern of seasonality. Independent correlates of seasonality were female gender (adjusted OR 1.27, 95% CI 1.01–1.61; p = 0.042), mild cognitive impairment (adjusted OR 1.51, 95% CI 1.16–1.97; p = 0.002), greater multimorbidity (OR 1.20, 95% CI 1.15–1.26 per Charlson Comorbidity Index Score; p

Objective: The objective of this study was to assess the cost-effectiveness of a long-term, nurse-led, multidisciplinary programme of home/clinic visits in preventing progressive cardiac dysfunction in patients at risk of developing de novo chronic heart failure (CHF). Methods: A trial-based analysis was conducted alongside a pragmatic, single-centre, open-label, randomized controlled trial of 611 patients (mean age: 66 years) with subclinical cardiovascular diseases (without CHF) discharged to home from an Australian tertiary referral hospital. A nurse-led home and clinic-based programme (NIL-CHF intervention, n = 301) was compared with standard care ( n=310) in terms of life-years, quality-adjusted life-years (QALYs) and healthcare costs. The uncertainty around the incremental cost and QALYs was quantified by bootstrap simulations and displayed on a cost-effectiveness plane. Results: During a median follow-up of 4.2 years, there were no significant between-group differences in life-years (−0.056, p=0.488) and QALYs (−0.072, p=0.399), which were lower in the NIL-CHF group. The NIL-CHF group had slightly lower all-cause hospitalization costs (AUD$2943 per person; p=0.219), cardiovascular-related hospitalization costs (AUD$1142; p=0.592) and a more pronounced reduction in emergency/unplanned hospitalization costs (AUD$4194 per person; p=0.024). When the cost of intervention was added to all-cause, cardiovascular and emergency-related readmissions, the reductions in the NIL-CHF group were AUD$2742 ( p=0.313), AUD$941 ( p=0.719) and AUD$3993 ( p=0.046), respectively. At a willingness-to-pay threshold of AUD$50,000/QALY, the probability of the NIL-CHF intervention being better-valued was 19%. Conclusions: Compared with standard care, the NIL-CHF intervention was not a cost-effective strategy as life-years and QALYs were slightly lower in the NIL-CHF group. However, it was associated with modest reductions in emergency/unplanned readmission costs.

Background Frequent readmissions are a hallmark of chronic heart failure (CHF). We sought to develop an absolute risk prediction model for unplanned cardiovascular readmissions following hospitalisation for CHF. Methods An inception cohort was obtained from the WHICH? trial, a prospective, multi-centre randomised controlled trial which was a head-to-head comparison of the efficacy of a home-based intervention versus clinic-based intervention for adults with CHF. A Cox's proportional hazards model (taking into account the competing risk of death) was used to develop a prediction model. Bootstrap methods were used to identify factors for the final model. Based on these data a nomogram was developed. Results Of the 280 participants in the WHICH? trial 37 (13%) were readmitted for a cardiovascular event (including CHF) within 28 days, and a further 149 (53%) were readmitted within 18 months for a cardiovascular event. In the proposed competing risk model, factors associated with an increased risk of hospitalisation for CHF were: age (HR 1.07, 95% CI 0.90-1.26) for each 10-year increase in age; living alone (HR 1.09, 95% CI 0.74-1.59); those with a sedentary lifestyle (HR 1.44, 95% CI, 0.92-2.25) and the presence of multiple co-morbid conditions (HR 1.69, 95% CI 0.38-7.58) for five or more co-morbid conditions (compared to individuals with one documented co-morbidity). The C-statistic of the final model was 0.80. Conclusion We have developed a practical model for individualising the risk of short-term readmission for CHF. This model may provide additional information for targeting and tailoring interventions and requires future prospective evaluation.

Aims The aim of this study was to determine the effectiveness of a long-term, nurse-led, multidisciplinary programme of home/clinic visits in preventing progressive cardiac dysfunction in individuals at risk of developing de novo chronic heart failure (CHF). Methods and results A pragmatic, single-centre (tertiary-referral hospital with specialist cardiological services), open-label, randomized controlled trial with blinded endpoint adjudication was carried out. In total, 624 cardiac inpatients (66 ± 11 years, 71% male, and 70% with CAD) were randomly allocated (1:1) to standard care or the study intervention. The intention-to-treat cohort comprised 310 standard care and 301 intervention participants. During 51.0 ± 8.2 months follow-up, 38/310 (12%) standard care [mean event-free survival 1865 days, 95% confidence interval (CI) 1817–1913 days] vs. 41/301 (14%) intervention participants (1855 days, 95% CI 1804–1906 days) experienced the primary composite endpoint of de novo CHF hospitalization or all-cause mortality (P = 0.574). Although there were no statistically significant differences in the rate of cardiovascular-related and emergency hospitalizations, the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) group accumulated 478 (0.214 ± 0.70 vs. 0.095 ± 0.284 days/participant/month; P = 0.052) and 1097 fewer days of hospital stay (0.391 ± 1.80 vs. 0.199 ± 0.47 days/participant/month; P = 0.023), respectively, compared with standard care. The intervention group also showed better cardiac recovery on echocardiography at 3 years [81/226 (35.8%) vs. 56/225 (24.9%), odds ratio 1.44, 95% CI 1.08–1.92, P = 0.011]. Conclusions Relative to a high level of standard care, the NIL-CHF intervention was ineffective in preventing CHF and rehospitalization. On the other hand, it was associated with reduced hospital stay and improved cardiac function over the long term. Trial registration Australian New Zealand Clinical Trials Registry (No. 12608000022369)

Background A number of composite outcomes have been developed to capture the perspective of the patient, clinician and objective measures of health in assessing heart failure outcomes. To date there has been a limited examination in the composition of these outcomes. Methods and results Three commonly used scoring systems in heart failure trials: Packer's composite, Patient Journey and the African American Heart Failure Trial (A-HeFT) scores were compared in assessing outcomes from the Which heart failure intervention is most cost-effective & consumer friendly in reducing hospital care (WHICH(?)) Trial. Comparability and interpretability of these outcomes and the influence of each component to the final outcome were examined. Despite all three composite outcomes incorporating mortality, hospitalisation and quality of life (QoL), the contribution of each individual component to the final outcomes differed. The component with the most influence in deteriorating condition for the Packer's composite was hospitalisation (67.7%), while in Patient Journey it was QoL (61.5%) and for A-HeFT composite score it was mortality (45.4%). Conclusions The contribution made by each component varied in subtle, but important ways. This study emphasises the importance of understanding the value system of the composite outcomes to enable meaningful interpretation of results.

Purpose: Multi-attribute utility instruments (MAUIs) are widely used to measure utility weights. This study sought to compare utility weights of two popular MAUIs, the EQ-5D-3L and the SF-6D, and inform researchers in the selection of generic MAUI for use with cardiovascular (CVD) patients. Methods: Data were collected in the Young@Heart study, a randomised controlled trial of a nurse-led multidisciplinary home-based intervention compared to standard usual care. Participants (n = 598) completed the EQ-5D-3L and the SF-12v2, from which the SF-6D can be constructed, at baseline and at 24-month follow-up. This study examined discrimination, responsiveness, correlation and differences across the two instruments. Results: Both MAUIs were able to discriminate between the NYHA severity classes and recorded similar changes between the two time points although only SF-6D differences were significant. Correlations between the dimensions of the two MAUIs were low. There were significant differences between the two instruments in mild conditions but they were similar in severe conditions. Substantial ceiling and floor effects were observed. Conclusions: Our findings indicate that the EQ-5D and the SF-6D cover different spaces in health due to their classification systems. Both measures were capable of discriminating between severity groups and responsive to quality of life changes in the follow-up. It is recommended to use the EQ-5D-3L in severe and the SF-6D in mild CVD conditions.

This study aimed to determine the association of stage B heart failure (SBHF) and its constituent left ventricular (LV) abnormalities with trajectory of exercise capacity over time, and assess whether this association is modified by reversion of these LV abnormalities to normal.The LV abnormalities of SBHF may coincide with a reduction in exercise capacity that precedes the overt exercise intolerance of clinical heart failure (HF). Determining the predictive capacity of established and novel SBHF criteria for exercise capacity decline may improve HF risk stratification.LV structure/function (echocardiography) and exercise capacity (6-min walk distance [6MWD]) were assessed at baseline and 3-year follow-up in 268 patients from the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (all stage A [SAHF] or SBHF). Changes (Δ) in 6MWD were compared between SAHF and SBHF and across each of 4 constituent components of SBHF: LV hypertrophy, regional wall motion abnormality(ies) (RWMA), left ventricular systolic dysfunction (LVSD) (ejection fraction 45%) and elevated early diastolic filling/annular velocity ratio (E/e' ≥15).Δ6MWD was similar in those with SAHF (n = 141) and SBHF (n = 127; -5 m [95% confidence interval (CI): -21 to +11 m]; covariate-adjusted). However, within the setting of SBHF there was substantive heterogeneity; that is, reductions in 6MWD were observed with persistent elevated E/e' (-34 m [95% CI: -62 to -6 m]) and persistent LVSD (-41 m [95% CI: -74 to -8 m]), but not with LV hypertrophy (+17 m [95% CI: -15 to +49 m) or RWMA (+5 m [-27 to +36 m]), nor in patients whose elevated E/e' or LVSD reverted to normal by 3 years (p0.10).Elevated E/e' is associated with a similar degree of exercise capacity decline to LVSD, supporting that both LV functional criteria be considered in distinguishing SBHF from SAHF. That reversion of either manifestation of LV dysfunction was associated with preserved exercise capacity advocates targeting of these factors by HF preventive interventions.

Background: Multimorbidity has an adverse effect on health outcomes in hospitalized individuals with chronic heart failure (CHF), but the modulating effect of multidisciplinary management is unknown. Objective: The aim of this study was to test the hypothesis that increasing morbidity would independently predict an increasing risk of 30-day readmission despite multidisciplinary management of CHF. Methods: We studied patients hospitalized for any reason with heart failure receiving nurse-led, postdischarge multidisciplinary management. We profiled a matrix of expected comorbidities involving the most common coexisting conditions associated with CHF and examined the relationship between multimorbidity and 30-day all-cause readmission. Results: A total of 830 patients (mean age 73 +/- 13 years and 65% men) were assessed. Multimorbidity was common, with an average of 6.6 +/- 2.4 comorbid conditions with sex-based differences in prevalence of 4 of 10 conditions. Within 30 days of initial hospitalization, 216 of 830 (26%) patients were readmitted for any reason. Greater multimorbidity was associated with increasing readmission (4%-44% for those with 0-1 to 8-9 morbid conditions; adjusted odds ratio, 1.25; 95% confidence interval, 1.13-1.38) for each additional condition. Three distinct classes of patient emerged: class 1-diabetes, metabolic, and mood disorders; class 2-renal impairment; and class 3-low with relatively fewer comorbid conditions. Classes 1 and 2 had higher 30-day readmission than class 3 did (adjusted P < .01 for both comparisons). Conclusions: These data affirm that multimorbidity is common in adult CHF inpatients and in potentially distinct patterns linked to outcome. Overall, greater multimorbidity is associated with a higher risk of 30-day all-cause readmission despite high-quality multidisciplinary management. More innovative approaches to target-specific clusters of multimorbidity are required to improve health outcomes in affected individuals.

Lipid emulsions have been proposed to suppress hunger and food intake. Whilst there is no consensus on optimal structural properties or mechanism of action, small particle size (small-PS) stable emulsions may have greatest efficacy. Fabuless®, a commercial lipid emulsion reported in some studies to decrease energy intake (EI), is a small-PS, ‘hard’ fat emulsion comprising highly saturated palm oil base (PS, 82 nm). To determine whether small-PS dairy lipid emulsions can enhance satiety, firstly, we investigated 2 ‘soft’ fat dairy emulsions generated using dairy and soy emulsifying agents (PS, 114 nm and 121 nm) and a non-emulsified dairy control. Secondly, we investigated a small-PS palmolein based ‘hard’ fat emulsion (fractionated palm oil, PS, 104 nm) and non-emulsified control. This was a 6 arm, randomized, cross-over study in 18 lean men, with test lipids delivered in a breakfast meal: (i) Fabuless® emulsion (FEM); (ii) dairy emulsion with dairy emulsifier (DEDE); (iii) dairy emulsion with soy lecithin emulsifier (DESE); (iv) dairy control (DCON); (v) palmolein emulsion with dairy emulsifier (PEDE); (vi) palmolein control (PCON). Participants rated postprandial appetite sensations using visual analogue scales (VAS), and ad libitum energy intake (EI) was measured at a lunch meal 3.5 h later. Dairy lipid emulsions did not significantly alter satiety ratings or change EI relative to dairy control (DEDE, 4035 kJ; DESE, 3904 kJ; DCON, 3985 kJ; P > 0.05) nor did palm oil based emulsion relative to non-emulsified control (PEDE, 3902 kJ; PCON, 3973 kJ; P > 0.05). There was no evidence that small-PS dairy lipid emulsions or commercial Fabuless altered short-term appetite or food intake in lean adults.

© The Author 2017. Aims To determine if an intensified form of heart failure management programme (INT-HF-MP) based on individual profiling is superior to standard management (SM) in reducing health care costs during 12-month follow-up (primary endpoint). Methods and results A multicentre randomized trial involving 787 patients (full analysis set) discharged from four tertiary hospitals with chronic HF who were randomized to SM (n = 391) or INT-HF-MP (n = 396). Mean age was 74 ± 12 years, 65% had HF with a reduced ejection fraction (31.4 ± 8.9%) and 14% were remote-dwelling. Study groups were well matched. According to Green, Amber, Red Delineation of rIsk And Need in HF (GARDIAN-HF) profiling, regardless of location, patients in the INT-HF-MP received a combination of face-to-face (home visits) and structured telephone support (STS); only 9% ('low risk') were designated to receive the same level of management as the SM group. The median cost in 2017 Australian dollars (A$1 equivalent to ∼EUR e0.7) of applying INT-HF-MP was significantly greater than SM ($152 vs. $121 per patient per month; P < 0.001), However, at 12 months, there was no difference in total health care costs for the INT-HF-MP vs. SM group (median $1579, IQR $644 to $3717 vs. $1450, IQR $564 to $3615 per patient per month, respectively). This reflected minimal differences in all-cause mortality (17.7% vs. 18.4%; P = 0.848) and recurrent hospital stay (18.6 ± 26.5 vs. 16.6 ± 24.8 days; P = 0.199) between the INT-HF-MP and SM groups, respectively. Conclusion During 12-months follow-up, an INT-HF-MP did not reduce healthcare costs or improve health outcomes relative to SM.

Background: The EQ-5D-3L, a generic multi-attribute utility instrument (MAUI), is widely employed to assist in economic evaluations in health care. The EQ-5D-3L lacks sensitivity when used in conditions such as cardiovascular disease (CVD). Although there are number of CVD specific quality of life instruments, currently, there are no CVD specific MAUIs. The aim of this study is to investigate the discriminative ability and responsiveness of the EQ-5D-3L and the Minnesota Living with Heart Failure Questionnaire (MLHF), a CVD specific quality of life instrument in a group of heart failure patients. Methods: The psychometric performance of the EQ-5D-3L and the MLHF was assessed using data from a randomised trial for a heart failure management intervention. The two instruments were compared for discrimination, responsiveness and agreement. The severity groups were defined using New York Heart Association functional classes. Results: The effect sizes for severe classes were generally similar showing good discrimination. The MLHF recorded better responsiveness between the time points than the EQ-5D-3L which was indicated by higher effect sizes and standardised response means. The change in MLHF summary scores between the time points was significant (p < 0.005; paired t-test). The overall agreement between the two measures was low. Conclusion: The low correlation indicates that the two classification systems cover different aspects of health space. Comparison of CVD specific instruments with other generic MAUIs such as EQ-5D-3L and AQOL-8D is recommended for further research.

Associations have been shown between consumption of bovine dairy and decreased prevalence of metabolic related disorders. Milk peptides may promote both angiotensin-I- converting enzyme (ACE) inhibition for blood pressure (BP) lowering and insulin action for better glycaemic control. Less is known of other metabolic parameters. The aim of this study was to investigate effects of dairy peptic casein hydrolysate (CH) on markers of cardiovascular disease (CVD) risk in (1) an apolipoproteinE (ApoE) - deficient mouse model of high-fat fed hypercholesterolaem- ia, and, (2) a clinical study of moderate overweight and hypercholesterolaemia. In Trial 1, ApoE-deficient mice were supplemented with high dose CH (~1g/kg body weight) in a randomised, 9-wk, parallel design intervention, and blood and tissue samples harvested. In Trial 2, 24 mildly hypercholesterolaemic men were supplemented with lower dose CH (~0.1g/kg body weight, 10g/day, 3-wks) and matched whey protein control (WP, 10g/day, 3-wks) in a randomised, 9-wk, cross-over design intervention. Diets were separated by a 3-wk washout. Fasting blood and urine samples were collected, and blood pressure (BP) measured weekly. Clinical trial registration number, ACTRN 12611001013954. In ApoE-deficient mice, administration of CH significantly inhibited circulating total cholesterol concentrations by 37% (TC, P

Background: Weight gain and hypoglycaemia are common adverse effects associated with anti-diabetic treatments. Aim: Our aim was to evaluate the long-term effects of adjunctive exenatide therapy on weight loss and glycaemic control in patients with type 2 diabetes. Methods: A review of medical records in a specialist diabetes clinic over 5 years identified 446 patients who were prescribed exenatide therapy. We examined change in glycosylated haemoglobin (HbA), weight, albumin-creatinine ratio and hypoglycaemic medication during 24 months follow up. Results: Subjects were aged 59 ± 10 years (49% women) and received exenatide in combination with oral agents and insulin (47%). During an average of 17 ± 14 months follow up, 51% (more women than men; odds ratio 1.69, 95% confidence interval 1.14-2.49) remained on treatment. Lack of efficacy (33%) and/or gastrointestinal (27%) side-effects were the main reasons for treatment cessation. At 24 months, there was a reduction in HbA of 0.7 ± 1.2% and weight loss of 4.3 ± 5.2kg. Change in HbA was similar regardless of concurrent insulin therapy, yet insulin was associated with greater weight reduction (4.8 ± 5.3 vs 3.8 ± 5.1kg, P = 0.016). Independent predictors of HbA response were higher baseline HbA, longer duration of diabetes and use of insulin or sulfonylureas at study end. Predictors of weight response were baseline use of insulin or thiazolidinediones, increased age, female sex and sulfonylurea or thiazolidinediones at study end. Longer exenatide treatment duration was favourable for reducing HbA and weight. Conclusions: Exenatide is effective in reducing HbA and weight, regardless of concurrent insulin, and in a specialist diabetes outpatient clinic, is recommended for use in clinical practice.

Background Comprehensive epidemiological data to describe the burden of heart failure (HF) in Australia remain lacking despite its importance as a major health issue. Herewith, we estimate the current and future burden of HF in Australia using best available data. Methods Australian-specific and the most congruent international epidemiological and health utilisation data were applied to the Australian population (adults aged ≥ 45 years, 8.9 of 22.7 million total population in 2014) on an age and sex-specific basis. We estimated the current incident and prevalent cases of clinically overt/symptomatic HF (predominately those with reduced ejection fraction), hospital activity (diagnosis of HF as a primary or secondary reason for admission) and health care costs in 2014 and future prevalence and burden of HF projected to 2030. Results We estimated that over 61,000 (6.9 per 1000 person-years) adult Australians aged ≥ 45 years (58 % women) are diagnosed with HF with clinically overt signs and symptoms every year. On a conservative basis, 480,000 (6.3 %, 95 % CI 2.6 to 10.0 %) Australians (66 % men) are now affected by the syndrome with > 150,000 hospitalisations in excess of 1 million days in hospital per annum. The annual cost of managing HF in the community is approximately $900 million and nearly $2.7 billion ($1.5 versus $1.2 billion, men versus women) when considering the additional cost of in-patient care. We predict that the prevalence and future burden of HF will continue to increase over the next 10–15 years to nearly 750,000 people with an estimated annual health care cost of $3.8 billion. Conclusions Australia is not immune to the growing magnitude and implications of a sustained epidemic of HF in an ageing population. However, its public health and economic burden will remain ill-defined until more definitive Australian-specific data are generated.

OBJECTIVE: To explore the psychosocial determinants and interhospital variability on a major acute cardiovascular event (MACE), during follow-up of a multicenter cohort of patients hospitalised with heart disease, participating in a nurse-led secondary prevention programme.METHODS: Outcome data were retrospectively analysed from 602 cardiac inpatients randomised to postdischarge standard care (n=296), or home-based intervention (n=306), with prolonged follow-up of individualised multidisciplinary support. Baseline psychosocial profiling comprised depressive status, health-related quality of life (HRQoL), social isolation and mild cognitive impairment (MCI). Multivariate analyses examined the independent correlates of a composite 2-year MACE rate of all-cause mortality and unplanned cardiovascular-related hospitalisation, according to gender.RESULTS: Participants were aged 70±10 years, 431 (72%) were men and 377 (63%) had coronary artery disease. During 2-year follow-up, 165 (27%) participants (114 men, 51 women; p=0.431) experienced a MACE. Independent correlates of a MACE in men were depressive status (OR 1.95, 95% CI 1.06 to 3.58; p=0.032), low physical HRQoL (OR 0.98, 95% CI 0.96 to 1.00; p=0.027) and increasing comorbidity (OR 1.14, 95% CI 1.04 to 1.25; p=0.004). In women, age (OR 1.06, 95% CI 1.02 to 1.12; p=0.008), MCI (OR 2.38, 95% CI 1.09 to 5.18; p=0.029) and hospital site predicted a MACE (OR 2.32, 95% CI 1.09 to 4.93; p=0.029).CONCLUSIONS: Psychological determinants, cognitive impairment and responses to secondary prevention are different for men and women with heart disease and appear to modulate cardiovascular-specific outcomes. Early detection of psychosocial factors through routine screening and gender-specific secondary prevention is encouraged.TRIAL REGISTRATION NUMBER: 12608000014358.

Objectives The goal of this study was to make a head-to-head comparison of 2 common forms of multidisciplinary chronic heart failure (CHF) management. Background Although direct patient contact appears to be best in delivering CHF management overall, the precise form to optimize health outcomes is less clear. Methods This prospective, multicenter randomized controlled trial with blinded endpoint adjudication comprised 280 hospitalized CHF patients (73% male, age 71 ± 14 years, and 73% with left ventricular ejection fraction ≤45%) randomized to home-based intervention (HBI) or specialized CHF clinic–based intervention (CBI). The primary endpoint was all-cause, unplanned hospitalization or death during 12- to 18-month follow-up. Secondary endpoints included type/duration of hospitalization and healthcare costs. Results The primary endpoint occurred in 102 of 143 (71%) HBI versus 104 of 137 (76%) CBI patients (adjusted hazard ratio [HR]: 0.97 [95% confidence interval (CI): 0.73 to 1.30], p = 0.861): 96 (67.1%) HBI versus 95 (69.3%) CBI patients had an unplanned hospitalization (p = 0.887), and 31 (21.7%) versus 38 (27.7%) died (p = 0.252). The median duration of each unplanned hospitalization was significantly less in the HBI group (4.0 [interquartile range (IQR): 2.0 to 7.0] days vs. 6.0 [IQR: 3.5 to 13] days; p = 0.004). Overall, 75% of all hospitalization was attributable to 64 (22.9%) patients, of whom 43 (67%) were CBI patients (adjusted odds ratio: 2.55 [95% CI: 1.37 to 4.73], p = 0.003). HBI was associated with significantly fewer days of all-cause hospitalization (−35%; p = 0.003) and from cardiovascular causes (−37%; p = 0.025) but not for CHF (−24%; p = 0.218). Consequently, healthcare costs ($AU3.93 vs. $AU5.53 million) were significantly less for the HBI group (median: $AU34 [IQR: 13 to 81] per day vs. $AU52 [17 to 140] per day; p = 0.030). Conclusions HBI was not superior to CBI in reducing all-cause death or hospitalization. However, HBI was associated with significantly lower healthcare costs, attributable to fewer days of hospitalization. (Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care [WHICH?]; ACTRN12607000069459 )

Circulating levels of adiponectin are low in obesity and metabolic disorders associated with increasing fat mass including insulin resistance and dyslipidemia. Body fat stores may be positively related to intake of dietary fat, but little is known of mechanisms by which serum adiponectin may be regulated through diet. We investigated acute effects of a high-fat load and changes in fatty acid saturation on circulating adiponectin and associated mediators of inflammation including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP).A high-fat test meal (59 +/- 4 g fat; 71% of energy as fat) containing a high ( approximately 71:29) or low ( approximately 55:45) ratio of saturated:unsaturated fatty acids was given at breakfast on two occasions. Blood samples were collected at 0 (baseline), 1, 3, and 6 h for measurement of adiponectin, IL-6, TNF-alpha, and high-sensitivity CRP. A fat-exclusion lunch, snack, and dinner were also given and blood samples collected at 10 and 24 h.Eighteen healthy, lean men completed the trial. There was no evidence of acute change in circulating adiponectin in response to the lipid bolus or a differential effect of fatty acid saturation on adiponectin, high-sensitivity CRP, or IL-6 (P0.05). IL-6 increased over 6 h on both treatments (time, P0.05). TNF-alpha decreased on the high saturated:unsaturated fatty acid treatment (treatment by time, P0.05). There were no significant correlations between circulating adiponectin and insulin on either dietary treatment in these normoglycemic subjects.Acute changes in the content of saturated and unsaturated fatty acids had no adverse effect on postprandial circulation of the adipose-related factors adiponectin, IL-6, TNF-alpha, or high-sensitivity CRP.

Background Early clinical studies showed the commercial lipid emulsion Fabuless™ to decrease energy intake (EI) and prevent weight regain, but later studies have failed to confirm this finding. Where appetite suppression has been observed it is commonly attributed to the ileal brake, where emulsified fats pass undigested to the distal small intestine and promote later satiety, but satiety profiles suggest possible transient effects within 15 min. The aim of this study was to determine whether this emulsion promotes short-term satiation and meal termination. Methods In a randomised cross-over intervention 18 lean men were given 4 lipid preloads immediately prior to a breakfast meal, during which ad libitum food consumption, time to meal termination and VAS-rated appetite scores were measured. Preloads were given as lipid emulsion and lipid control, both alone as a ‘shot’ and combined with a dairy yoghurt: (i) lipid emulsion alone (LE, Fabuless™ 4.2g lipid, 0.2 MJ), (ii) lipid control alone (LC, 4 .2g lipid, 0.2 MJ), (iii) LE + yoghurt (1.2 MJ), (iv) LC + yoghurt (1.2 MJ). Results Whilst both yoghurt preloads suppressed EI at breakfast relative to the ‘shots’, as expected, neither lipid emulsion suppressed EI or triggered more rapid meal termination when compared to energy matched lipid controls (P > 0.05). There was also no difference in VAS-assessed appetite scores between emulsion and control, for either preload. Conclusions When consumed with a meal there was no evidence in lean men that this commercial lipid emulsion promotes satiation or suppresses short-term food intake.

Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu(2+) ions are strongly pro-oxidant, and chelatable-Cu(II) is increased in the diabetic heart. We reported previously that treatment by Cu(II)-selective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu(II) in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu(2+)-mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-beta1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose](plasma) in diabetic animals. LV and aortic mRNAs corresponding to TGF-beta1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS](tissue) were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-beta/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.

We recently showed that treatment with the CuII-selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu]serum and HbA1c. Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic CuII. We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic CuII.