Short sleep duration is associated with risk of future diabetes but not cardiovascular disease: a prospective study and meta-analysis

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%.The Sax Institute; Cancer Council New South Wales; the National Heart Foundation of Australia (New South Wales Division); The New South Wales Ministry of Health; Beyondblue: the National Depression Initiative; Ageing, Disability and Home Care, New South Wales Family and Community Services; the Australian Red Cross Blood Service; Uniting Care Ageing; the Australian National Health and Medical Research Council

Fruit and vegetable consumption and all-cause mortality: evidence from a large Australian cohort study

BACKGROUND: There is growing evidence for a relationship between fruit and vegetable consumption and all-cause mortality. Few studies, however, specifically explored consuming raw versus cooked vegetables in relation to health and mortality outcomes. The purpose of this study was to examine the relation of all-cause mortality with: a) fruit and vegetable consumption, either combined or separately; b) the consumption of raw versus cooked vegetables in a large cohort of Australian middle-aged and older adults. METHODS: The sample included 150,969 adults aged 45 years and over from the 45 and Up Study, a prospective cohort study conducted in New South Wales, Australia. Self-reported baseline questionnaire data (2006–09) were linked to mortality data up to June 2014. Fruit and vegetable consumption was assessed by validated short questions. Crude and adjusted hazard ratios were calculated using Cox proportional hazard models. Covariates included socio-demographic characteristics, health-related and dietary variables. RESULTS: During a mean follow-up of 6.2 years, 6038 (4 %) participants died from all causes. In the fully adjusted models, increasing consumption of fruit and vegetables combined was associated with reductions in all-cause mortality, with the highest risk reduction seen up to 7 serves/day or more of fruit and vegetables (P for trend = 0.002, hazard ratio for highest versus lowest consumption quartile: 0.90; 95 % confidence interval: 0.84, 0.97). Separate consumption of fruit and vegetables, as well as consumption of raw or cooked vegetables, were associated with a reduced risk of all-cause mortality in the crude and minimally adjusted models (all P for trend <0.05). With the exception of raw vegetables, these associations remained significant in the fully adjusted models (all P for trend <0.05). Age and sex were significant effect modifiers of the association between fruit and vegetable consumption and all-cause mortality. CONCLUSIONS: Fruit and vegetable consumption were inversely related to all-cause mortality in this large Australian cohort. Further studies examining the effects of raw versus cooked vegetables are needed

Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study

BACKGROUND 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. METHODS AND FINDINGS 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). CONCLUSIONS 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.JC has received research grants from Servier, administered through the University of Sydney and The George Institute, as principal investigator for the ADVANCE trial and ADVANCE-ON post trial follow-up study, and have received honoraria from Servier for speaking about ADVANCE at Scientific meetings. PM has received payment from Pfizer for giving a lecture on the treatment of pulmonary hypertension. All other authors have declared that no competing interests exis

Association between pre-existing cardiovascular disease, mortality and cardiovascular outcomes in hospitalised patients with COVID-19

BackgroundPre-existing cardiovascular disease and cardiovascular risk factors are common in patients with COVID-19 and there remain concerns for poorer in-hospital outcomes in this cohort. We aimed to analyse the relationship between pre-existing cardiovascular disease, mortality and cardiovascular outcomes in patients hospitalised with COVID-19 in a prospective, multicentre observational study.MethodThis prospective, multicentre observational study included consecutive patients of age ≥18 in their index hospitalisation with laboratory-proven COVID-19 in Australia. Patients with suspected but not laboratory-proven COVID-19 and patients with no available past medical history were excluded. The primary exposure was pre-existing cardiovascular disease, defined as a composite of coronary artery disease, heart failure or cardiomyopathy, atrial fibrillation or flutter, severe valvular disease, peripheral arterial disease and stroke or transient ischaemic attack. The primary outcome was in-hospital mortality. Secondary outcomes were clinical cardiovascular complications (new onset atrial fibrillation or flutter, high-grade atrioventricular block, sustained ventricular tachycardia, new heart failure or cardiomyopathy, pericarditis, myocarditis or myopericarditis, pulmonary embolism and cardiac arrest) and myocardial injury.Results1,567 patients (mean age 60.7 (±20.5) years and 837 (53.4%) male) were included. Overall, 398 (25.4%) patients had pre-existing cardiovascular disease, 176 patients (11.2%) died, 75 (5.7%) had clinical cardiovascular complications and 345 (37.8%) had myocardial injury. Patients with pre-existing cardiovascular disease had significantly increased in-hospital mortality (aOR: 1.76 95% CI: 1.21–2.55, p = 0.003) and myocardial injury (aOR: 3.27, 95% CI: 2.23–4.79, p &lt; 0.001). There was no significant association between pre-existing cardiovascular disease and in-hospital clinical cardiovascular complications (aOR: 1.10, 95% CI: 0.58–2.09, p = 0.766). On mediation analysis, the indirect effect and Sobel test were significant (p &lt; 0.001), indicating that the relationship between pre-existing cardiovascular disease and in-hospital mortality was partially mediated by myocardial injury. Apart from age, other cardiovascular risk factors such as diabetes, hypercholesterolemia and hypertension had no significant impact on mortality, clinical cardiovascular complications or myocardial injury.ConclusionsPre-existing cardiovascular disease is associated with significantly higher mortality in patients hospitalised with COVID-19. This relationship may be partly explained by increased risk of myocardial injury among patients with pre-existing cardiovascular disease which in turn is a marker associated with higher mortality

Inflammatory Markers and Outcomes in Cardiovascular Disease

In a commentary on two new research studies in PLoS Medicine, Leonard Kritharides discusses the role of inflammatory markers in predicting cardiovascular outcomes and patients' responses to treatment

Sphingomyelin phosphodiesterase Acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages

Cholesterol-loaded foam cell macrophages are prominent in atherosclerotic lesions and play complex roles in both inflammatory signaling and lipid metabolism, which are underpinned by large scale reprogramming of gene expression. We performed a microarray study of primary human macrophages that showed that transcription of the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene is up-regulated after cholesterol loading. SMPDL3A protein expression in and secretion from primary macrophages are stimulated by cholesterol loading, liver X receptor ligands, and cyclic AMP, and N-glycosylated SMPDL3A protein is detectable in circulating blood. We demonstrate for the first time that SMPDL3A is a functional phosphodiesterase with an acidic pH optimum. We provide evidence that SMPDL3A is not an acid sphingomyelinase but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by liver X receptor-stimulated human macrophages. Extracellular nucleotides such as ATP may activate pro-inflammatory responses in immune cells. Increased expression and secretion of SMPDL3A by cholesterol-loaded macrophage foam cells in lesions may decrease local concentrations of pro-inflammatory nucleotides and potentially represent a novel anti-inflammatory axis linking lipid metabolism with purinergic signaling in atherosclerosis

TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis.

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

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors JACC State-of-the-Art Review

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed