Inflammation and heart failure: a two-sample Mendelian randomization study.

BACKGROUND: It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach. METHODS: Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method. RESULTS: We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias. CONCLUSION: This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias.

Causal Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Peripheral Artery Disease: A Mendelian Randomization Approach.

Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2-sample inverse-variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European-ancestry genomic summary data (P<5×10-8) for type 2 diabetes, lipid-fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million-Veteran-Program genome-wide association studies (cases=31 307, controls=211 753, 72% European-ancestry) and the GoLEAD-SUMMIT genome-wide association studies (11 independent genome-wide association studies, European-ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni-significant (P<0.00294), consistent over PAD-cohorts/sensitivity analyses), suggestive (P value: 0.00294-0.05, associations in 1 PAD-cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low-density lipoprotein cholesterol, triglyceride-levels, alcohol consumption, and inverse associations for high-density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low-density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid-fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low-density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.

Alcohol Consumption and Cardiovascular Disease Risk: Placing New Data in Context.

PURPOSE OF REVIEW: A clear link between excessive alcohol consumption and cardiovascular disease (CVD) has been established, but no consensus exists on the effects of moderate alcohol consumption on CVD. RECENT FINDINGS: A lower risk of coronary heart disease and myocardial infarction among moderate drinkers compared to abstainers has been consistently observed in epidemiological studies and meta-analyses of these studies. However, ambiguity remains on the effect of alcohol on other CVDs and all-cause mortality. Short-term randomized controlled trials (RCT) have identified potentially beneficial effects of alcohol consumption on cardiovascular risk factors, but studies investigating genetic polymorphisms that influence alcohol consumption (i.e., Mendelian randomization) have yielded inconclusive results. To date, a long-term RCT providing causal evidence is lacking but urgently needed. Triangulation of evidence from different study designs, including long-term RCTs, pragmatic trials and the evaluation of policy measures, combined will lead to the best available evidence.

Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies.

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Hypertension: A Mendelian Randomization Study.

Hypertension is a major risk factor for cardiovascular disease and mortality. To identify targets for the prevention of hypertension and its associated disease burden, we used the 2-sample Mendelian randomization method to investigate the causal associations of 18 cardiovascular risk factors and lifestyle behaviors with hypertension. From European-descent genome-wide association studies, we selected genetic variants (P<5×10-8) for type 2 diabetes, fasting glucose, lipids, body mass index, smoking, alcohol and coffee consumption, physical activity, sleep duration, insomnia, and educational level. We extracted the genetic associations with hypertension from 2 European cohorts: the FinnGen Study (15 870 cases and 74 345 controls) and UK Biobank (54 358 cases and 408 652 controls). The inverse-variance weighted method was used as main analysis method. Genetically predicted triglycerides (pooled odds ratio [OR] per 1 SD, 1.17 [1.10-1.25]), body mass index (OR per 1 SD, 1.42 [1.37-1.48]), alcohol dependence (OR, 1.10 [1.06-1.13]), and insomnia (OR, 1.17 [1.13-1.20]) were associated with a higher odds of hypertension. Higher genetically predicted high-density lipoprotein cholesterol (OR per 1 SD, 0.88 [0.83-0.94]) and educational level (OR per 1 SD, 0.56 [0.54-0.59]) were associated with a lower odds of hypertension. Suggestive evidence was obtained for type 2 diabetes, smoking initiation and alcohol consumption with a higher hypertension odds, and longer sleep duration with a lower hypertension odds. This Mendelian randomization study identified high-density lipoprotein cholesterol, triglycerides, body mass index, alcohol dependence, insomnia, and educational level as causal risk factors for hypertension. This implicates that these modifiable risk factors are important targets in the prevention of hypertension.

Alcohol consumption patterns across Europe and adherence to the European guidelines in coronary patients: Findings from the ESC-EORP EUROASPIRE V survey.

BACKGROUND AND AIMS: Alcohol consumption is an important risk factor for cardiovascular morbidity and mortality worldwide. The highest levels of alcohol consumption are observed in Europe, where alcohol as contributing cause of coronary heart disease (CHD) is also most significant. We aimed to describe alcohol consumption patterns across European regions and adherence to the current guidelines in patients with a recent CHD event. METHODS: The ESC-EORP survey (EUROASPIRE V) has been conducted in 2016-2017 at 131 centers in 27 European countries in 7350 patients with a recent CHD. Median alcohol consumption, as well as the proportion of abstainers and excessive drinkers (i.e. >70 g/week for women and >140 for men, as recommended by the European guidelines on cardiovascular prevention), was calculated for each region. To assess adherence to guidelines, proportions of participants who were advised to reduce excessive alcohol consumption and participants who were incorrectly not advised were calculated per region. RESULTS: Mean age was 64 years (SD: 9.5), 75% were male. Abstention rates were 53% in males and 77% in females, whereas excessive drinking was reported by 9% and 5% of them, respectively. Overall, 57% of the participants were advised to reduce alcohol consumption. In the total population, 3% were incorrectly not advised, however, this percentage differed per region (range: 1%-9%). In regions where alcohol consumption was highest, participants were less often advised to reduce their consumption. CONCLUSION: In this EUROASPIRE V survey, the majority of CHD patients adhere to the current drinking guidelines, but substantial heterogeneity exists between European regions.

Modifiable lifestyle factors and heart failure: A Mendelian randomization study.

BACKGROUND: Lifestyle factors may be important targets in the prevention of heart failure. The current knowledge on the relationship between lifestyle factors and heart failure originates mostly from observational studies. The objective of this study was to investigate causal associations of multiple lifestyle factors with heart failure risk by using Mendelian randomization. METHODS: We obtained summary statistics data for single nucleotide polymorphisms associated with the following 5 lifestyle factors at genome-wide significance in genome-wide association studies of European-descent individuals: smoking, alcohol consumption, coffee consumption, physical activity, and sleep duration. The corresponding data for heart failure were acquired from a genome-wide association study comprising 47,309 cases and 930,014 controls of European ancestry. For the primary analyses, we used the inverse-variance weighted method. RESULTS: Genetic predisposition to smoking initiation (ever smoked regularly) was robustly associated with a higher odds of heart failure (odds ratio: 1.28; 99% CI: 1.21-1.35). Genetically predicted longer sleep duration was associated with a lower odds of heart failure (odds ratio per hour/day: 0.73; 99% CI: 0.60-0.89). We found no associations of alcohol consumption, coffee consumption, and physical activity with heart failure. CONCLUSIONS: This Mendelian randomization study showed that smoking initiation increases heart failure risk, whereas longer sleep duration decreases the risk of heart failure. Sleep duration should be regarded as novel risk factor in heart failure prevention guidelines. The potential causal role of alcohol and coffee consumption and physical activity for heart failure warrants further investigation in future larger Mendelian randomization analyses.

Urinary Ethyl Glucuronide as Measure of Alcohol Consumption and Risk of Cardiovascular Disease: A Population-Based Cohort Study.

Background Moderate alcohol consumption has been associated with a lower risk of cardiovascular disease (CVD) and all-cause mortality compared with heavy drinkers and abstainers. To date, studies have relied on self-reported consumption, which may be prone to misclassification. Urinary ethyl glucuronide (EtG) is an alcohol metabolite and validated biomarker for recent alcohol consumption. We aimed to examine and compare the associations of self-reported alcohol consumption and EtG with CVD and all-cause mortality. Methods and Results In 5676 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study cohort, EtG was measured in 24-hour urine samples and alcohol consumption questionnaires were administered. Participants were followed up for occurrence of first CVD and all-cause mortality. Cox proportional hazards regression models, adjusted for age, sex, and CVD risk factors, were fitted for self-reported consumption, divided into 5 categories: abstention, 1 to 4 units/month (reference), 2 to 7 units/week, 1 to 3 units/day, and ≥4 units/day. Similar models were fitted for EtG, analyzed as both continuous and categorical variables. Follow-up times differed for CVD (8 years; 385 CVD events) and all-cause mortality (14 years; 724 deaths). For both self-reported alcohol consumption and EtG, nonsignificant trends were found toward J-shaped associations between alcohol consumption and CVD, with higher risk in the lowest (hazard ratio for abstention versus 1-4 units/month, 1.42; 95% CI, 1.02-1.98) and highest drinking categories (hazard ratio for ≥4 units/day versus 1-4 units/month, 1.11; 95% CI, 0.68-1.84). Neither self-report nor EtG was associated with all-cause mortality. Conclusions Comparable associations with CVD events and all-cause mortality were found for self-report and EtG. This argues for the validity of self-reported alcohol consumption in epidemiologic research.

Moderate and heavy alcohol consumption are prospectively associated with decreased left ventricular ejection fraction: The Hoorn Study.

BACKGROUND AND AIMS: Data on the prospective relationship of alcohol consumption at more moderate levels with systolic and diastolic function are scarce. We aimed to examine the prospective association of alcohol consumption with echocardiographic measures of cardiac structure and function, in individuals with and without type 2 diabetes (T2DM). METHODS AND RESULTS: We included 778 participants from the Hoorn Study (aged 68.4 ± 7.2 years, 49% women), a population-based prospective cohort study, oversampled for people with impaired glucose metabolism or T2DM. Self-reported alcohol consumption was collected at baseline with a validated food-frequency questionnaire and categorized into: none (0/week), light (>0-≤30 g/week), light-to-moderate (>30-≤70 g/week), moderate (>70-≤140 g/week), and heavy drinkers (>140 g/week). Echocardiography was performed at baseline (N = 778) and after 8 years follow-up (N = 404). Multiple linear regression was used to study the association between alcohol consumption and echocardiographic measures (left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI)), adjusted for confounders. Moderate and heavy alcohol consumption were associated with a decreased LVEF of -3.91% (CI: -7.13;-0.69) for moderate and -4.77% (-8.18;-1.36) for heavy drinkers compared to light drinkers. No associations were found between alcohol consumption, LVMI and LAVI. Modified Poisson regression showed a trend that higher alcohol consumption amounts were associated with a higher risk of incident systolic dysfunction (LVEF≤50%) (P-for-trend 0.058). CONCLUSION: The findings provide longitudinal evidence that moderate and heavy alcohol consumption are associated with decreased LVEF and trend towards a higher risk of incident LV systolic dysfunction, compared to light drinkers.

Urinary Ethyl Glucuronide Can Be Used as a Biomarker of Habitual Alcohol Consumption in the General Population.

BACKGROUND: Alcohol consumption is a frequently studied risk factor for chronic diseases, but many studies are hampered by self-report of alcohol consumption. The urinary metabolite ethyl glucuronide (EtG), reflecting alcohol consumption during the past 72 h, is a promising objective marker, but population data are lacking. OBJECTIVE: The objective of this study was to assess the reliability of EtG as a marker for habitual alcohol consumption compared with self-report and other biomarkers in the general population. METHODS: Among 6211 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, EtG concentrations were measured in 24-h urine samples. EtG was considered positive when concentrations were ≥100 ng/mL. Habitual alcohol consumption was self-reported by questionnaire (categories: no/almost never, 1-4 units per month, 2-7 units per week, 1-3 units per day or ≥4 units per day). Plasma HDL cholesterol concentration, erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT) were determined as indirect biomarkers of alcohol consumption. Sensitivity, specificity, positive and negative predictive value, and proportions of agreement between reported consumption and EtG were calculated. To test the agreement of EtG concentration and alcohol consumption in categories, linear regression analysis was performed. In addition, the association between EtG concentrations and indirect biomarkers was analyzed. RESULTS: Mean age was 53.7 y, and 52.9% of participants men. Of the self-reported abstainers, 92.3% had an EtG concentration <100 ng/mL. Sensitivity was 66.3%, positive predictive value was 96.3%, and negative predictive value was 47.4%. The proportion of positive agreement was 78.5%, and the proportion of negative agreement was 62.7%. EtG concentrations were linearly associated with higher categories of alcohol consumption (P-trend < 0.001), adjusted for age, sex, and renal function. EtG was positively related to MCV, HDL cholesterol, and GGT but not to AST and ALT concentrations. CONCLUSIONS: This study shows that urinary EtG is in reasonable agreement with self-reported alcohol consumption and therefore can be used as an objective marker of habitual alcohol consumption in the general population.