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Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is secreted from many cells throughout the body. ApoE is best known for its role in lipoprotein metabolism. Recent studies underline the association of circulating lipoprotein-associated apoE levels and the development for cardiovascular disease (CVD). Besides its well-established role in pathology of CVD, it is also implicated in neurodegenerative diseases and recent new data on adipose-produced apoE point to a novel metabolic role for apoE in obesity. The regulation of apoE production and secretion is remarkably cell and tissue specific. Here, we summarize recent insights into the differential regulation apoE production and secretion by hepatocytes, monocytes/macrophages, adipocytes, and the central nervous system and relevant variations in apoE biochemistry and function.

Epidemiologic studies have observed association between short sleep duration and both cardiovascular disease (CVD) and type 2 diabetes, although these results may reflect confounding by pre-existing illness. This study aimed to determine whether short sleep duration predicts future CVD or type 2 diabetes after accounting for baseline health. Baseline data for 241,949 adults were collected through the 45 and Up Study, an Australian prospective cohort study, with health outcomes identified via electronic database linkage. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals. Compared to 7h sleep, <6h sleep was associated with incident CVD in participants reporting ill-health at baseline (HR=1.38 [95% CI: 1.12-1.70]), but not after excluding those with baseline illness and adjusting for baseline health status (1.03 [0.88-1.21]). In contrast, the risk of incident type 2 diabetes was significantly increased in those with <6h versus 7h sleep, even after excluding those with baseline illness and adjusting for baseline health (HR=1.29 [1.08-1.53], P=0.004). This suggests the association is valid and does not simply reflect confounding or reverse causation. Meta-analysis of ten prospective studies including 447,124 participants also confirmed an association between short sleep and incident diabetes (1.33 [1.20-1.48]). Obtaining less than 6 hours of sleep each night (compared to 7 hours) may increase type 2 diabetes risk by approximately 30%.

ObjectivesTo describe the outcomes and associations of pericardial disease, with a particular focus on the outcomes of patients admitted with primary or secondary pericardial disease.DesignRetrospective observational study.SettingAll public and private hospitals in New South Wales, Australia.ParticipantsHospitalised patients with pericardial disease admitted from 2004 to 2021 that was (a) a primary diagnosis or (b) a secondary diagnosis.MeasuresMortality both in-hospital and during several years of available follow-up.ResultsOut of 45 446 patients diagnosed with pericardial disease, under half (46.8%) had pericardial disease as the primary reason for hospitalisation. Patients in whom pericardial disease was the primary compared with the secondary diagnosis were more commonly male (68.2% vs 59.1%), younger (median 51.2 years vs 66.0 years) and less comorbid (age-adjusted median Charlson Comorbidity Index 1 vs 4). In patients with pericardial disease, adjusted in-hospital mortality was fivefold lower if this was the primary diagnosis (OR 0.21, p<0.001). Malignancy affected 19% of the population and after adjustment was associated with a much higher in-hospital mortality for patients with a primary (OR 4.33) or secondary diagnosis of pericardial disease (OR 2.67). Other negative prognostic factors included older age, liver disease, chronic kidney disease, pulmonary hypertension, heart failure and chronic obstructive pulmonary disease.ConclusionsPatients with pericardial disease have a low in-hospital mortality of about 1% if this was the primary diagnosis. However, patients in whom it was a secondary diagnosis, especially in the presence of comorbidities such as malignancy, had a much worse prognosis.

Whether a bias exists in the implantation of permanent pacemakers (PPI) and complications according to sex and age in the Australian population is unclear. We examined the prevalence of PPI from January-2009 to December-2018 from datasets held by the New South Wales (NSW) Centre-for-Health-Record-Linkage, including patient's characteristics and in-hospital complications. All analysis was stratified by sex and age by decade. A total of 28,714 admissions involved PPI (40% women). The mean PPI rate (±standard-deviation) and median age (interquartile range) was 2,871±242 per-annum and 80yrs (73-86yrs), respectively. At the same time-period, the mean NSW population size was 7,487,393±315,505 persons (50% women; n = 3,773,756±334,912). The mean annual age-adjusted rate of PPI was 125.5±11.6 per-100,000-men, compared to 63.4±14.3 per-100,000-women (P<0.01). The mean annual rate of PPI increased from 2009-2017 by 0.9±3.3% in men, compared to 0.4±4.4% in women (P<0.01) suggesting a widening disparity. Total non-fatal in-hospital complications was higher in women compared to men (8.2% vs 6.6%, P<0.01), and this persisted throughout study period even after adjusting for multiple covariates. Overall, in-hospital mortality was low (0.73%) and similar between sexes. In a statewide Australian population exceeding 7 million, PPI rates were consistently nearly two-fold higher for men compared to women over 10-years, with an apparently widening disparity, that was not explained by age. Overall complication rates were higher in women. Future studies should examine the aetiology behind this disparity in PPI rates, as well as its complications.

Epidemiologic studies have shown an inverse correlation between high-density lipoprotein (HDL) cholesterol (HDL-C) levels and cardiovascular disease outcomes. However, the hypothesis of a causal relationship between HDL-C and cardiovascular disease has been challenged by genetic and clinical studies. Serum cholesterol efflux capacity (CEC) is an important measure of HDL function in humans. Recent large clinical studies have shown a correlation between in vitro CEC and cardiovascular disease prevalence and incidence, which appears to be independent of HDL-C concentration. The present review summarizes recent large clinical studies and introduces important methodological considerations. Further studies are required to standardize and establish the reproducibility of this measure of HDL function and clarify whether modulating CEC will emerge as a useful therapeutic target.

ObjectivesThe aim of the study was to evaluate mortality and morbidity outcomes following open-heart isolated tricuspid valve surgery (TVSx) with medium to long-term follow-up.DesignRetrospective cohort study.SettingNew South Wales public and private hospital admissions between 1 January 2002 and 30 June 2018.ParticipantsA total of 537 patients underwent open isolated TVSx during the study period.Primary and secondary outcome measuresPrimary outcome was all-cause mortality tracked from the death registry to 31 December 2018. Secondary morbidity outcomes, including admission for congestive cardiac failure (CCF), new atrial fibrillation (AF), infective endocarditis (IE), pulmonary embolism (PE) and insertion of a permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD), were tracked from the Admitted Patient Data Collection database. Independent mortality associations were determined using the Cox regression method.ResultsA total of 537 patients underwent open isolated TVSx (46% male): median age (IQR) was 63.5 years (43.9–73.8 years) with median length of stay of 16 days (10–31 days). Main cardiovascular comorbidities were AF (54%) and CCF (42%); 67% had rheumatic tricuspid valve. In-hospital and total mortality were 7.4% and 39.3%, respectively (mean follow-up: 4.8 years). Cause-specific deaths were evenly split between cardiovascular and non-cardiovascular causes. Predictors of mortality included a history of CCF (HR=1.78, 95% CI 1.33 to 2.38, p<0.001) and chronic pulmonary disease (HR=2.66, 95% CI 1.63 to 4.33, p<0.001). In-hospital PPM rate was 10.0%. At 180 days, 53 (9.9%) patients were admitted for CCF, 25 (10.1%) had new AF, 7 (1.5%) had new IE and <1% had PE, post-discharge PPM or ICD insertion.ConclusionOpen isolated TVSx carries significant mortality risk, with decompensated CCF and new AF the most common morbidities encountered after surgery. This report forms a benchmark to compare outcomes with newer percutaneous tricuspid interventions.

Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes. We conducted a prospective population-based Australian study (the 45 and Up Study) linking questionnaire data from 2006-2009 with hospitalisation and death data to 30 June and 31 Dec 2010 respectively for 95,038 men aged ≥45 y. Cox proportional hazards models were used to examine the relationship of reported severity of erectile dysfunction to all-cause mortality and first CVD-related hospitalisation since baseline in men with and without previous CVD, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and hypertension and/or hypercholesterolaemia treatment. There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60, 95% CI 1.31-1.95), heart failure (8.00, 2.64-24.2), peripheral vascular disease (1.92, 1.12-3.29), \"other\" CVD (1.26, 1.05-1.51), all CVD combined (1.35, 1.19-1.53), and all-cause mortality (1.93, 1.52-2.44). For men with previous CVD, corresponding RRs (95% CI) were 1.70 (1.46-1.98), 4.40 (2.64-7.33), 2.46 (1.63-3.70), 1.40 (1.21-1.63), 1.64 (1.48-1.81), and 2.37 (1.87-3.01), respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66, 1.22-2.26), atrioventricular and left bundle branch block (6.62, 1.86-23.56), and (peripheral) atherosclerosis (2.47, 1.18-5.15), with no significant difference in risk for conditions such as primary hypertension (0.61, 0.16-2.35) and intracerebral haemorrhage (0.78, 0.20-2.97). These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment. The utility of erectile dysfunction as a clinical risk prediction tool requires specific testing.

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

Background βeta-2 glycoprotein I (β2GPI, Apolipoprotein H) is a plasma glycoprotein best known as a major autoantigen in autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), both of which confer elevated cardiovascular risk. Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood. Methods We investigated β2GPI’s influence on lipoprotein profiles using β2GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from β2GPI-deficient patients and aged and sex matched controls. Lipoprotein fractions were analyzed for cholesterol and apolipoprotein content, and protein interactions were assessed by co-immunoprecipitation. Results In animal studies, female β2GPI KO mice—but not males—displayed significantly increased total plasma cholesterol on a HF diet and greater cholesterol content within HDL fractions. Apo E was enriched in HDL fractions from female KO mice under both NC and HF diets, and plasma Apo E was elevated in HF-fed female KOs. In WT females on HF diet, β2GPI was enriched in HDL fractions, and β2GPI co-immunoprecipitated with Apo E. In human studies, the β2GPI-deficient female patient exhibited increased HDL cholesterol, a shift toward larger HDL particles, and enriched Apo E in HDL fractions relative to controls. Co-immunoprecipitation confirmed β2GPI–Apo E interaction in human plasma, with binding requiring Domain V of β2GPI. Conclusions Our findings identify β2GPI as a sex-specific regulator of HDL metabolism. In females, β2GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking β2GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting β2GPI–Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts. Highlights β2GPI (Apolipoprotein H) regulates HDL cholesterol levels in a sex-specific manner, significantly impacting lipid metabolism in females but not males. Female β2GPI knockout mice exhibit elevated total cholesterol and enrichment of ApoE in HDL particles, especially under high-fat diet conditions. β2GPI directly interacts with ApoE, with domain V of β2GPI mediating this binding in both mouse and human plasma. A rare β2GPI-deficient female patient showed larger HDL particle size, mirroring the murine phenotype. Findings suggest β2GPI is a novel modulator of ApoE-containing HDL particles in females, with potential relevance to cardiovascular and autoimmune diseases, and possibly Alzheimer’s disease risk. Layperson Summary This study uncovers a new role for a blood protein called β2-glycoprotein I (also known as Apolipoprotein H) in cholesterol metabolism, specifically in females. β2-glycoprotein I is best known for its involvement in autoimmune diseases such as lupus and antiphospholipid syndrome — conditions that mostly affect women and increase cardiovascular risk. Using both mouse models and rare human samples, we found that the absence of β2-glycoprotein I leads to increased levels of certain high-density lipoprotein (HDL) particles in females, but not in males. These HDL particles also showed higher levels of another key protein called Apolipoprotein E (ApoE), which is involved in cholesterol transport and linked to diseases like Alzheimer’s. However, not all HDL particles have the same biological effects — some may be protective, while others could contribute to disease. Our findings suggest that β2-glycoprotein I may play an important role in maintaining the balance of HDL particle types in females. Disrupting this balance could affect how cholesterol is processed in the body, with implications for heart and brain health. This research helps explain important sex differences in disease risk and opens new paths for targeted treatment strategies, particularly for women.

In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.