Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis.

BACKGROUND: Guidelines advocate changes in fatty acid consumption to promote cardiovascular health. PURPOSE: To summarize evidence about associations between fatty acids and coronary disease. DATA SOURCES: MEDLINE, Science Citation Index, and Cochrane Central Register of Controlled Trials through July 2013. STUDY SELECTION: Prospective, observational studies and randomized, controlled trials. DATA EXTRACTION: Investigators extracted data about study characteristics and assessed study biases. DATA SYNTHESIS: There were 32 observational studies (530,525 participants) of fatty acids from dietary intake; 17 observational studies (25,721 participants) of fatty acid biomarkers; and 27 randomized, controlled trials (103,052 participants) of fatty acid supplementation. In observational studies, relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain ω-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for ω-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids when the top and bottom thirds of baseline dietary fatty acid intake were compared. Corresponding estimates for circulating fatty acids were 1.06 (CI, 0.86 to 1.30), 1.06 (CI, 0.97 to 1.17), 0.84 (CI, 0.63 to 1.11), 0.94 (CI, 0.84 to 1.06), and 1.05 (CI, 0.76 to 1.44), respectively. There was heterogeneity of the associations among individual circulating fatty acids and coronary disease. In randomized, controlled trials, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for α-linolenic, 0.94 (CI, 0.86 to 1.03) for long-chain ω-3 polyunsaturated, and 0.89 (CI, 0.71 to 1.12) for ω-6 polyunsaturated fatty acid supplementations. LIMITATION: Potential biases from preferential publication and selective reporting. CONCLUSION: Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats. PRIMARY FUNDING SOURCE: British Heart Foundation, Medical Research Council, Cambridge National Institute for Health Research Biomedical Research Centre, and Gates Cambridge.

Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of epidemiological studies investigating the association of arsenic, lead, cadmium, mercury, and copper with cardiovascular disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and Web of Science searched up to December 2017. REVIEW METHODS: Studies reporting risk estimates for total cardiovascular disease, coronary heart disease, and stroke for levels of arsenic, lead, cadmium, mercury, or copper were included. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks were standardised to a common scale and pooled across studies for each marker using random effects meta-analyses. RESULTS: The review identified 37 unique studies comprising 348 259 non-overlapping participants, with 13 033 coronary heart disease, 4205 stroke, and 15 274 cardiovascular disease outcomes in aggregate. Comparing top versus bottom thirds of baseline levels, pooled relative risks for arsenic and lead were 1.30 (95% confidence interval 1.04 to 1.63) and 1.43 (1.16 to 1.76) for cardiovascular disease, 1.23 (1.04 to 1.45) and 1.85 (1.27 to 2.69) for coronary heart disease, and 1.15 (0.92 to 1.43) and 1.63 (1.14 to 2.34) for stroke. Relative risks for cadmium and copper were 1.33 (1.09 to 1.64) and 1.81 (1.05 to 3.11) for cardiovascular disease, 1.29 (0.98 to 1.71) and 2.22 (1.31 to 3.74) for coronary heart disease, and 1.72 (1.29 to 2.28) and 1.29 (0.77 to 2.17) for stroke. Mercury had no distinctive association with cardiovascular outcomes. There was a linear dose-response relation for arsenic, lead, and cadmium with cardiovascular disease outcomes. CONCLUSION: Exposure to arsenic, lead, cadmium, and copper is associated with an increased risk of cardiovascular disease and coronary heart disease. Mercury is not associated with cardiovascular risk. These findings reinforce the importance of environmental toxic metals in cardiovascular risk, beyond the roles of conventional behavioural risk factors.

Alcohol intake in relation to non-fatal and fatal coronary heart disease and stroke: EPIC-CVD case-cohort study.

OBJECTIVE: To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. DESIGN: Multicentre case-cohort study. SETTING: A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. PARTICIPANTS: 32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. MAIN OUTCOME MEASURES: Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). RESULTS: There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. CONCLUSIONS: Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.

Maternal weight status, diet, and supplement use as determinants of breastfeeding and complementary feeding: a systematic review and meta-analysis.

CONTEXT: Infant feeding practices are influenced by maternal factors. OBJECTIVE: The aim of this review is to examine the associations between maternal weight status or dietary characteristics and breastfeeding or complementary feeding. DATA SOURCES: A systematic literature search of the Embase, Cochrane Library, Google Scholar, MEDLINE, PubMed, and Web of Science databases was performed. STUDY SELECTION: Interventional and cohort studies in healthy mothers and infants that reported on maternal weight status, diet, or supplement use were selected. DATA EXTRACTION: Outcomes assessed included delayed onset of lactogenesis; initiation, exclusivity, duration, and cessation of breastfeeding; and timing of complementary feeding. DATA ANALYSIS: Eighty-one studies were included. Maternal underweight, diet, and supplement use were not associated with infant feeding practices. Obese women had a relative risk of failure to initiate breastfeeding (risk ratio [RR] = 1.23; 95%CI, 1.03-1.47) and a delayed onset of lactogenesis (RR  =  2.06; 95%CI, 1.18-3.61). The RR for breastfeeding cessation was 1.11 (95%CI, 1.07-1.15) per increase in category of body mass index. CONCLUSIONS: Prevention of obesity in women of reproductive age, as well as counseling of obese women after delivery, could be targeted to improve infant feeding practices.

Risk of All-Cause Mortality in Alcohol-Dependent Individuals: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Alcohol dependence (AD) carries a high mortality burden, which may be mitigated by reduced alcohol consumption. We conducted a systematic literature review and meta-analysis investigating the risk of all-cause mortality in alcohol-dependent subjects. METHODS: MEDLINE, MEDLINE In-Process, Embase and PsycINFO were searched from database conception through 26th June 2014. Eligible studies reported all-cause mortality in both alcohol-dependent subjects and a comparator population of interest. Two individuals independently reviewed studies. Of 4540 records identified, 39 observational studies were included in meta-analyses. FINDINGS: We identified a significant increase in mortality for alcohol-dependent subjects compared with the general population (27 studies; relative risk [RR] = 3.45; 95% CI [2.96, 4.02]; p < 0.0001). The mortality increase was also significant compared to subjects qualifying for a diagnosis of alcohol abuse or subjects without alcohol use disorders (AUDs). Alcohol-dependent subjects continuing to drink heavily had significantly greater mortality than alcohol-dependent subjects who reduced alcohol intake, even if abstainers were excluded (p < 0.05). INTERPRETATION: AD was found to significantly increase an individual's risk of all-cause mortality. While abstinence in alcohol-dependent subjects led to greater mortality reduction than non-abstinence, this study suggests that alcohol-dependent subjects can significantly reduce their mortality risk by reducing alcohol consumption.

Simvastatin treatment upregulates intestinal lipid secretion pathways in a rodent model of the metabolic syndrome.

OBJECTIVE: Statins are widely used for the treatment of hyperlipidemia to reduce cardiovascular disease (CVD) risk. Intriguingly, recent reports suggest that whilst statins are effective in reducing hepatic cholesterol synthesis, they in turn may up-regulate intestinal cholesterol absorption. The direct effects and/or mechanisms of this phenomenon remain largely unknown. The aim of this study was to investigate the potential for statins to increase intestinal lipid absorption and/or secretion in a rodent model of the metabolic syndrome (MetS). METHODS AND RESULTS: Mets JCR:LA-cp rats received a 1% cholesterol diet containing Simvastatin (0.01% w/w), for 8 weeks. Fasting and postprandial plasma biochemical profile was assessed using enzymatic assays and a modified apoB48 (chylomicron; CM) western blotting protocol. Statin treatment reduced fasting plasma TG (-49%), cholesterol (-24%) and postprandial plasma apoB48 (-58%). The intestinal secretion of lipids into mesenteric lymph was assessed using lymph fistulae procedures. Interestingly, MetS rats treated with statin secreted greater cholesterol (1.9-fold) and TG (1.5-fold) per apoB48 particle, into mesenteric lymph. This was shown to be as a result of simvastatin-induced increase in intestinal cholesterol absorption (31.5%). Experiments using in vivo inhibition of lipoprotein lipase (LPL; poloxamer-407) demonstrated statin treatment reduced hepatic cholesterol secretion (-49%), but significantly increased hepatic (73%) TG secretion in MetS rats. Statin treatment also increased the expression of genes involved in lipid synthesis (Hmgcr, Srebp1, Fas, Acc; 33-67%) and reduced those involved in efflux (Abca1, Abcg8; -36 to 73%) in enterocytes and liver of MetS rats versus untreated control. CONCLUSIONS: In a rodent model of MetS, statin treatment adversely up-regulates intestinal lipid secretion as a result of increased intestinal cholesterol absorption, and increases the intestinal expression of genes involved in lipid synthesis; effects which may confound clinical benefits to remnant dyslipidemia.

Arterial retention of remnant lipoproteins ex vivo is increased in insulin resistance because of increased arterial biglycan and production of cholesterol-rich atherogenic particles that can be improved by ezetimibe in the JCR:LA-cp rat.

BACKGROUND: Literature supports the "response-to-retention" hypothesis-that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance. METHODS AND RESULTS: Arteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls. CONCLUSIONS: Increased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.

Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis.

OBJECTIVE: To clarify associations of fish consumption and long chain omega 3 fatty acids with risk of cerebrovascular disease for primary and secondary prevention. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Studies published before September 2012 identified through electronic searches using Medline, Embase, BIOSIS, and Science Citation Index databases. ELIGIBILITY CRITERIA: Prospective cohort studies and randomised controlled trials reporting on associations of fish consumption and long chain omega 3 fatty acids (based on dietary self report), omega 3 fatty acids biomarkers, or supplementations with cerebrovascular disease (defined as any fatal or non-fatal ischaemic stroke, haemorrhagic stroke, cerebrovascular accident, or transient ischaemic attack). Both primary and secondary prevention studies (comprising participants with or without cardiovascular disease at baseline) were eligible. RESULTS: 26 prospective cohort studies and 12 randomised controlled trials with aggregate data on 794,000 non-overlapping people and 34,817 cerebrovascular outcomes were included. In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease for 2-4 servings a week versus ≤ 1 servings a week was 0.94 (95% confidence intervals 0.90 to 0.98) and for ≥ 5 servings a week versus 1 serving a week was 0.88 (0.81 to 0.96). The relative risk for cerebrovascular disease comparing the top thirds of baseline long chain omega 3 fatty acids with the bottom thirds for circulating biomarkers was 1.04 (0.90 to 1.20) and for dietary exposures was 0.90 (0.80 to 1.01). In the randomised controlled trials the relative risk for cerebrovascular disease in the long chain omega 3 supplement compared with the control group in primary prevention trials was 0.98 (0.89 to 1.08) and in secondary prevention trials was 1.17 (0.99 to 1.38). For fish or omega 3 fatty acids the estimates for ischaemic and haemorrhagic cerebrovascular events were broadly similar. Evidence was lacking of heterogeneity and publication bias across studies or within subgroups. CONCLUSIONS: Available observational data indicate moderate, inverse associations of fish consumption and long chain omega 3 fatty acids with cerebrovascular risk. Long chain omega 3 fatty acids measured as circulating biomarkers in observational studies or supplements in primary and secondary prevention trials were not associated with cerebrovascular disease. The beneficial effect of fish intake on cerebrovascular risk is likely to be mediated through the interplay of a wide range of nutrients abundant in fish.

ApoA-1 infusion reduces arterial cholesterol and myocardial lesions in a rat model of cardiac dysfunction and insulin resistance.

OBJECTIVE: Low plasma high-density lipoprotein cholesterol (HDL-C) concentration is associated with the metabolic syndrome (MetS) and increased prevalence of cardiovascular disease (CVD). Animal and human studies report infusion of apolipoprotein A-1 (apoA-1) can reduce endothelial dysfunction, and/or induce regression of atherosclerosis. However, the direct mechanisms underlying the vascular benefits of either apoA-1 or HDL-C remain unclear. In this study, we assessed the ability of reconstituted HDL (rHDL) to improve vascular complications of MetS, including left ventricular (LV)-hypertrophy, arterial cholesterol deposition and myocardial lesion development. METHODS AND RESULTS: Obese insulin resistant (IR) JCR:LA-cp rats were infused with rHDL (0.4 mg/kg) over 3 days before assessing cardiac function (Echocardiography) at days 7 and 50 post-infusion, as well as haematoxylin and eosin staining of myocardial lesions at day 50. Acute ex vivo arterial cholesterol deposition was assessed with acute infusion of rHDL ex-vivo. Infusion of rHDL partially corrected abnormal diastolic compliance (18%; *p<0.05) and improved parameters of cardiac function in IR rats. Further, acute rHDL infusion in carotid vessels reduced remnant lipoprotein associated-cholesterol deposition (30-86%; **p<0.01) ex vivo in IR and male Wistar rats and reduced (41%; *p<0.05) the frequency of early-stage myocardial lesions in IR rats. CONCLUSION: Short-term infusion of rHDL may beneficially reduce chronic vascular sequelae of MetS, including temporary improvement in LV-dysfunction, acute reduction of acute arterial cholesterol deposition and the development of early-stage myocardial lesions in the JCR:LA-cp rat.

New insights into how the intestine can regulate lipid homeostasis and impact vascular disease: frontiers for new pharmaceutical therapies to lower cardiovascular disease risk.

In recent years, evidence has emerged that the intestine is a significant regulator of systemic cholesterol homeostasis and can contribute to raised plasma cholesterol concentration. In this review we provide a context for the role the intestine may have in cardiovascular disease during conditions of chronic disease (insulin resistance, obesity). In particular, we highlight the physiological role of the intestine in lipid absorption, identify novel elements in enterocyte molecular biology, review the concept that chylomicrons and their remnants contribute to atherogenesis during chronic disease, and address new principles of chylomicron overproduction during conditions of insulin resistance including the associated hormonal control of the intestine during these conditions. Finally, we raise the issue of a growing need for novel lipid-lowering pharmaceutical therapies that target intestinal lipid metabolism.

Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis.

OBJECTIVE: To evaluate the association of chocolate consumption with the risk of developing cardiometabolic disorders. DESIGN: Systematic review and meta-analysis of randomised controlled trials and observational studies. DATA SOURCES: Medline, Embase, Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, reference lists of relevant studies to October 2010, and email contact with authors. STUDY SELECTION: Randomised trials and cohort, case-control, and cross sectional studies carried out in human adults, in which the association between chocolate consumption and the risk of outcomes related to cardiometabolic disorders were reported. DATA EXTRACTION: Data were extracted by two independent investigators, and a consensus was reached with the involvement of a third. The primary outcome was cardiometabolic disorders, including cardiovascular disease (coronary heart disease and stroke), diabetes, and metabolic syndrome. A meta-analysis assessed the risk of developing cardiometabolic disorders by comparing the highest and lowest level of chocolate consumption. RESULTS: From 4576 references seven studies met the inclusion criteria (including 114,009 participants). None of the studies was a randomised trial, six were cohort studies, and one a cross sectional study. Large variation was observed between these seven studies for measurement of chocolate consumption, methods, and outcomes evaluated. Five of the seven studies reported a beneficial association between higher levels of chocolate consumption and the risk of cardiometabolic disorders. The highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease (relative risk 0.63 (95% confidence interval 0.44 to 0.90)) and a 29% reduction in stroke compared with the lowest levels. CONCLUSIONS: Based on observational evidence, levels of chocolate consumption seem to be associated with a substantial reduction in the risk of cardiometabolic disorders. Further experimental studies are required to confirm a potentially beneficial effect of chocolate consumption.