Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Blood Levels of Organochlorine Contaminants Mixtures and Cardiovascular Disease.

Importance: Cardiovascular toxic effects derived from high exposures to individual organochlorine compounds are well documented. However, there is no evidence on low but continuous exposure to combined organochlorine compounds in the general population. Objective: To evaluate the association of combined exposure to several organochlorine compounds, including organochlorine pesticides and polychlorinated biphenyls, with incident cardiovascular disease (CVD) in the general population. Design, Setting, and Participants: This prospective nested case-control study included data from 2 cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-Year-Olds (60YO), with matched case-control pairs based on age, sex, and sample date. Baseline blood sampling occurred from November 2003 to September 2009 (SMC-C) and from August 1997 to March 1999 (60YO), with follow-up through December 2017 (SMC-C) and December 2014 (60YO). Participants with myocardial infarction or ischemic stroke were matched with controls for composite CVD evaluation. Data were analyzed from September 2020 to May 2023. Exposures: A total of 25 organochlorine compounds were measured in blood at baseline by gas chromatography-triple quadrupole mass spectrometry. For 7 compounds, more than 75% of the samples were lower than the limit of detection and not included. Main Outcomes and Measures: Incident cases of primary myocardial infarction and ischemic stroke were ascertained via linkage to the National Patient Register (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I21 and I63). The quantile-based g-computation method was used to estimate the association between the combined exposure to several organochlorine compounds and composite CVD. Results: Of 1528 included participants, 1024 (67.0%) were female, and the mean (SD) age was 72 (7.0) years in the SMC-C and 61 (0.1) years in the 60YO. The odds ratio of composite CVD was 1.71 (95% CI, 1.11-2.64) per 1-quartile increment of total organochlorine compounds mixture. Organochlorinated pesticides were the largest contributors, and ß-hexachlorocyclohexane and transnonachlor had the highest impact. Most of the outcome was not explained by disturbances in the main cardiometabolic risk factors, ie, high body mass index, hypertension, lipid alteration, or diabetes. Conclusions and Relevance: In this prospective nested case-control study, participants with higher exposures to organochlorines had an increased probability of experiencing a cardiovascular event, the major cause of death worldwide. Measures may be required to reduce these exposures.

Antibodies against malondialdehyde among 60-year-olds: prediction of cardiovascular disease.

Malondialdehyde (MDA) is generated in oxidized LDL. It forms covalent protein adducts, and is recognized by antibodies (anti-MDA). We previously studied IgM anti-MDA, and here we focus on IgG, IgG1 and IgG2 anti-MDA in predicting cardiovascular disease (CVD). We determined, by ELISA, anti-MDA in a 7-year follow-up of 60-year-old men and women from Stockholm County (2039 men, 2193 women). We identified 210 incident CVD cases (defined as new events of myocardial infarction (MI), and hospitalization for angina pectoris) and ischemic stroke, and 620 age- and sex-matched controls. IgG anti-MDA was not associated with CVD. Median values only differed significantly for IgG1 anti-MDA among men, with lower levels among cases than controls (p = 0.039). High IgG1 anti-MDA (above 75th percentile) was inversely associated with CVD risk after adjustment for smoking, body mass index, type 2 diabetes, hyperlipidemia, and hypertension, (OR and 95% CI: 0.59; 0.40-0.89). After stratification by sex, this association emerged in men (OR and 95% CI: 0.46; 0.27-0.77), but not in women. IgG2 anti-MDA were associated with protection in the whole group and among men though weaker than IgG1 anti-MDA. IgG2 anti-MDA above the 75th percentile was associated with an increased risk of MI/angina in women (OR and 95% CI: 2.57; (1.08-6.16)). IgG1 and less so IgG2 anti-MDA are protection markers for CVD and MI/angina in the whole group and among men. However, IgG2 anti-MDA was a risk marker for MI/angina among women. These findings could have implications for both prediction and therapy.

Cross-Sectional Gene-Smoking Interaction Analysis in Relation to Subclinical Atherosclerosis-Results From the IMPROVE Study.

BACKGROUND: Smoking is associated with carotid intima-media thickness (C-IMT). However, knowledge about how genetics may influence this association is limited. We aimed to perform nonhypothesis driven gene-smoking interaction analyses to identify potential genetic variants, among those included in immune and metabolic platforms, that may modify the effect of smoking on carotid intima-media thickness. METHODS: We used baseline data from 1551 men and 1700 women, aged 55 to 79, included in a European multi-center study. Carotid intima-media thickness maximum, the maximum of values measured at different locations of the carotid tree, was dichotomized with cut point values ≥75, respectively. Genetic data were retrieved through use of the Illumina Cardio-Metabo- and Immuno- Chips. Gene-smoking interactions were evaluated through calculations of Synergy index (S). After adjustments for multiple testing, P values of <2.4×10-7 for S were considered significant. The models were adjusted for age, sex, education, physical activity, type of diet, and population stratification. RESULTS: Our screening of 207 586 SNPs available for analysis, resulted in the identification of 47 significant gene-smoking synergistic interactions in relation to carotid intima-media thickness maximum. Among the significant SNPs, 28 were in protein coding genes, 2 in noncoding RNA and the remaining 17 in intergenic regions. CONCLUSIONS: Through nonhypothesis-driven analyses of gene-smoking interactions, several significant results were observed. These may stimulate further research on the role of specific genes in the process that determines the effect of smoking habits on the development of carotid atherosclerosis.

Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis.

BACKGROUND: We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. METHODS: The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Immuno chips. Replication was attempted in three independent studies and a meta-analysis was performed using a random model. RESULTS: In IMPROVE, each unit increase in plasma IL-8 was associated with an increase in median c-IMT measures (all p<0·03) in multivariable analyses. Linear regression identified rs117518778 and rs8057084 as associated with IL-8 levels and with measures of c-IMT. The two SNPs were combined in an IL-8-increasing genetic risk that showed causality of IL-8 on c-IMT in IMPROVE and in the UK Biobank (n = 22,179). The effect of IL-8 on c-IMT measures was confirmed in PIVUS (n = 1,016) and MDCCC (n = 6,103). The association of rs8057084 with c-IMT was confirmed in PIVUS and UK Biobank with a pooled estimate effect (ß) of -0·006 with 95%CI (-0·008- -0·003). CONCLUSION: Our results indicate that genetic variants associated with plasma IL-8 also associate with c-IMT. However, we cannot infer causality of this association, as these variants lie outside of the IL8 locus.

Long-term prognosis after a first myocardial infarction: eight years follow up of the case-control study PAROKRANK.

Objective. To explore long-term cardiovascular outcomes and mortality in patients after a first myocardial infarction (MI) compared with matched controls in a contemporary setting. Methods. During 2010-2014 the Swedish study PAROKRANK recruited 805 patients <75 years with a first MI and 805 age-, gender-, and area-matched controls. All study participants were followed until 31 December 2018, through linkage with the National Patient Registry and the Cause of Death Registry. The primary endpoint was the first of a composite of all-cause death, non-fatal MI, non-fatal stroke, and heart failure hospitalization. Event rates in cases and controls were calculated using a Cox regression model, subsequently adjusted for baseline smoking, education level, and marital status. Kaplan-Meier curves were computed and compared by log-rank test. Results. A total of 804 patients and 800 controls (mean age 62 years; women 19%) were followed for a mean of 6.2 (0.2-8.5) years. The total number of primary events was 211. Patients had a higher event rate than controls (log-rank test p < .0001). Adjusted hazard ratio (HR) for the primary outcome was 2.04 (95% CI 1.52-2.73). Mortality did not differ between patients (n = 38; 4.7%) and controls (n = 35; 4.4%). A total of 82.5% patients and 91.3% controls were event-free during the follow up. Conclusions. In this long-term follow up of a contemporary, case-control study, the risk for cardiovascular events was higher in patients with a previous first MI compared with their matched controls, while mortality did not differ. The access to high quality of care and cardiac rehabilitation might partly explain the low rates of adverse outcomes.

Antibodies Against Phosphorylcholine Among 60-Year-Olds: Clinical Role and Simulated Interactions.

Aims: Antibodies against phosphorylcholine (anti-PC) are implicated as protection markers in atherosclerosis, cardiovascular disease (CVD), and other chronic inflammatory conditions. Mostly, these studies have been focused on IgM. In this study, we determined IgG, IgG1, and IgG2 anti-PC among 60-year-olds. Methods: Based on a 7-year follow-up of 60-year-olds (2,039 men and 2,193 women) from Stockholm County, we performed a nested case-control study of 209 incident CVD cases with 620 age- and sex-matched controls. Anti-PC was determined using ELISA. We predicted the binding affinity of PC with our fully human, in-house-produced IgG1 anti-PC clones (i.e., A01, D05, and E01) using the molecular docking and molecular dynamics simulation approach, to retrieve information regarding binding properties to PC. Results: After adjustment for confounders, IgG and IgG2 anti-PC showed some significant associations, but IgG1 anti-PC was much stronger as a protection marker. IgG1 anti-PC was associated with an increased risk of CVD below 33rd, 25th, and 10th percentile and of stroke below 33rd and 25th, and of myocardial infarction (MI) below 10th percentile. Among men, a strong association with stroke was determined below the 33rd percentile [HR 9.20, CI (2.22-38.12); p = 0.0022]. D05 clone has higher binding affinity followed by E01 and A01 using molecular docking and further have been confirmed during the course of 100 ns simulation. The stability of the D05 clone with PC was substantially higher. Conclusion: IgG1 anti-PC was a stronger protection marker than IgG anti-PC and IgG2 anti-PC and also separately for men. The molecular modeling approach helps in identifying the intrinsic properties of anti-PC clones and atomistic interactions with PC.

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case-Control Study in Sweden.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been associated with elevated cholesterol levels. However, data on incident cardiovascular disease (CVD) is lacking. OBJECTIVES: We investigated the association of exposure to PFAS with risk of myocardial infarction and stroke and, subsidiary, with baseline blood lipids. METHODS: This population-based nested case-control study included first incident myocardial infarction and stroke cases with matched controls from two Swedish cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-year-olds (60YO). Baseline blood sampling occurred during 2003-2009 and 1997-1999 with follow-up through 2017 and 2014 for the SMC-C and the 60YO, respectively. Eight plasma PFAS concentrations were measured using targeted liquid chromatography-triple quadrupole mass spectrometry. Five of these were quantifiable in both cohorts; individual values and their standardized sum were categorized into tertiles based on the controls. First incident myocardial infarction (n=345) and ischemic stroke (n=354) cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Controls were randomly selected from each cohort after matching for age, sex, and sample date. Baseline blood lipids were measured in plasma or serum after overnight fasting. RESULTS: Among the 1,528 case-control subjects, the mean (standard deviation) age was 66 (7.7) y and 67% of them were women. In multivariable-adjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher cholesterol and lower triglyceride levels among controls at baseline (n=631). The corresponding results were odds ratios=0.70 [95% confidence interval (CI): 0.53, 0.93] for CVD, 0.60 (95% CI: 0.39, 0.92) for myocardial infarction, and 0.83 (95% CI: 0.46, 1.50) for stroke. DISCUSSION: This study indicated that exposure to PFAS, although associated with increased cholesterol levels, did not associate with an increased risk of myocardial infarction, stroke, or their composite end point. The findings improve our knowledge on potential health effects of environmental contaminants in the CVD context. https://doi.org/10.1289/EHP9791.

Long-term risk of a major cardiovascular event by apoB, apoA-1, and the apoB/apoA-1 ratio-Experience from the Swedish AMORIS cohort: A cohort study.

BACKGROUND: Elevated apolipoprotein B (apoB) and elevated apoB/apoA-1 ratio increase the risk of myocardial infarction (MI) and stroke, whereas high apoA-1 is protective. We study how these apolipoproteins are associated with major adverse cardiovascular events (MACEs), whether apoA-1 contributes to this association, and whether abnormal values occur decades before such events develop. METHODS AND FINDINGS: In the Swedish AMORIS (Apolipoprotein-related MOrtality RISk) cohort study, 137,100 men and women aged 25-84 years were followed an average 17.8 years. ApoB, apoA-1, and the apoB/apoA-1 ratio were analysed in relation to MACEs (non-fatal MI, stroke, and cardiovascular [CV] mortality), yielding 22,473 events. Hazard ratios (HRs) were estimated using Cox regression. Kaplan-Meier estimates were used to investigate the relationship of MACEs with increasing quintiles of the apoB/apoA-1 ratio in all age groups for both sexes. In nested case-control analyses, cases were randomly matched to age- and sex-matched controls, yielding population trajectories for apolipoproteins. Increased level of apoB and increased apoB/apoA-1 ratio were associated with risk of MACE and all clinical sub-components in both men and women across all ages (10th versus first decile in both sexes combined: HR 1.7 for MACE and 2.7 for non-fatal MI). Decreased values of apoA-1 potentiated the impact of apoB at all levels of apoB (on average across apoB range: 40% increase in HR for MACE and 72% increase in HR for non-fatal MI), indicating that the apoB/apoA-1 ratio covers a broader range of persons with dyslipidaemia at risk than apoB alone. In both men and women, MACEs occurred earlier on average for each increasing quintile of the apoB/apoA-1 ratio. Individuals with the highest levels of apoB/apoA-1 ratio experienced CV events on average several years earlier than those with lower ratios. Higher apoB/apoA-1 ratio in cases of MACE versus controls was seen already about 20 years before the event. A limitation of this study was that adjustment for tobacco smoking and hypertension was only possible in a small validation study. CONCLUSIONS: An imbalance between apoB and apoA-1 resulting in an increased apoB/apoA-1 ratio is strongly associated with the outcome MACE and its sub-components, in both men and women of all ages. An increased apoB/apoA-1 ratio already 2 decades before events calls for early recognition and primary prevention. Simple evidence-based cut values should be considered in future cardiovascular guidelines.

Physical activity attenuates cardiovascular risk and mortality in men and women with and without the metabolic syndrome - a 20-year follow-up of a population-based cohort of 60-year-olds.

AIMS: The purpose of this study was to analyse the association of leisure-time physical activity of different intensities at baseline, and cardiovascular disease incidence, cardiovascular disease mortality and all-cause mortality in a population-based sample of 60-year-old men and women with and without established metabolic syndrome, for more than 20 years of follow-up. A secondary aim was to study which cardiometabolic factors may mediate the association between physical activity and long-term outcomes. METHODS: A total of 3693 participants (53% women) underwent physical examination and laboratory tests, completed an extensive questionnaire at baseline 1997-1999 and were followed until their death or until 31 December 2017. First-time cardiovascular disease events and death from any cause were ascertained through regular examinations of national registers. RESULTS: Metabolic syndrome prevalence was 23.0%. In metabolic syndrome participants, light physical activity attenuated cardiovascular disease incidence (hazard ratio = 0.71; 95% confidence interval 0.50-1.00) compared to sedentary (reference) after multi-adjustment. Moderate/high physical activity was inversely associated with both cardiovascular disease and all-cause mortality, but became non-significant after multi-adjustment. Sedentary non-metabolic syndrome participants had lower cardiovascular disease incidence (0.47; 0.31-0.72) but not significantly different cardiovascular disease (0.61; 0.31-1.19) and all-cause mortality (0.92; 0.64-1.34) compared to sedentary metabolic syndrome participants. Both light and moderate/high physical activity were inversely associated with cardiovascular disease and all-cause mortality in non-metabolic syndrome participants (p<0.05). There were significant variations in several central cardiometabolic risk factors with physical activity level in non-metabolic syndrome participants. Fibrinogen mediated the protective effects of physical activity in non-metabolic syndrome participants. CONCLUSION: Physical activity of different intensities attenuated cardiovascular risk and mortality in 60-year old men and women with metabolic syndrome during a 20-year follow-up.

Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population.

BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. CONCLUSIONS: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis.

BACKGROUND: We aimed to investigate the association of serum pentadecanoic acid (15:0), a biomarker of dairy fat intake, with incident cardiovascular disease (CVD) and all-cause mortality in a Swedish cohort study. We also systematically reviewed studies of the association of dairy fat biomarkers (circulating or adipose tissue levels of 15:0, heptadecanoic acid [17:0], and trans-palmitoleic acid [t16:1n-7]) with CVD outcomes or all-cause mortality. METHODS AND FINDINGS: We measured 15:0 in serum cholesterol esters at baseline in 4,150 Swedish adults (51% female, median age 60.5 years). During a median follow-up of 16.6 years, 578 incident CVD events and 676 deaths were identified using Swedish registers. In multivariable-adjusted models, higher 15:0 was associated with lower incident CVD risk in a linear dose-response manner (hazard ratio 0.75 per interquintile range; 95% confidence interval 0.61, 0.93, P = 0.009) and nonlinearly with all-cause mortality (P for nonlinearity = 0.03), with a nadir of mortality risk around median 15:0. In meta-analyses including our Swedish cohort and 17 cohort, case-cohort, or nested case-control studies, higher 15:0 and 17:0 but not t16:1n-7 were inversely associated with total CVD, with the relative risk of highest versus lowest tertile being 0.88 (0.78, 0.99), 0.86 (0.79, 0.93), and 1.01 (0.91, 1.12), respectively. Dairy fat biomarkers were not associated with all-cause mortality in meta-analyses, although there were ≤3 studies for each biomarker. Study limitations include the inability of the biomarkers to distinguish different types of dairy foods and that most studies in the meta-analyses (including our novel cohort study) only assessed biomarkers at baseline, which may increase the risk of misclassification of exposure levels. CONCLUSIONS: In a meta-analysis of 18 observational studies including our new cohort study, higher levels of 15:0 and 17:0 were associated with lower CVD risk. Our findings support the need for clinical and experimental studies to elucidate the causality of these relationships and relevant biological mechanisms.

Long-term exposure to low-level ambient air pollution and incidence of stroke and coronary heart disease: a pooled analysis of six European cohorts within the ELAPSE project.

BACKGROUND: Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and warm-season ozone (O3) with the incidence of stroke and acute coronary heart disease. METHODS: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. FINDINGS: From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8-19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM2·5 (hazard ratio 1·10 [95% CI 1·01-1·21] per 5 µg/m3 increase), NO2 (1·08 [1·04-1·12] per 10 µg/m3 increase), and black carbon (1·06 [1·02-1·10] per 0·5 10-5/m increase), whereas coronary heart disease incidence was only associated with NO2 (1·04 [1·01-1·07]). Warm-season O3 was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM2·5 and NO2 remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 µg/m3 for PM2·5 and 40 µg/m3 for NO2. INTERPRETATION: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values. FUNDING: Health Effects Institute.

IL6 trans-signaling associates with ischemic stroke but not with atrial fibrillation.

BACKGROUND: Pro-inflammatory processes underlie ischemic stroke, albeit it is largely unknown if they selectively associate with the risk of atherothrombotic or cardioembolic ischemic stroke. Here we analyze whether pro-inflammatory interleukin (IL) 6 trans-signaling, is associated with the risk of ischemic stroke and underlying atrial fibrillation (AF). METHODS: During a 20-year follow-up, 203 incident ischemic strokes were recorded from national registers in the cohort of 60-year-old men and women from Stockholm (n = 4232). The risk of ischemic stroke associated with circulating IL6 trans-signaling, assessed by a ratio between the pro-inflammatory binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex (B/T ratio), was estimated by Cox regression and expressed as hazard ratio (HR) with a 95% confidence interval (CI) in the presence or absence of AF. Risk estimates were adjusted for cardiovascular risk factors and anticoagulant treatment. In a secondary analysis, the association of IL6 trans-signaling with the risk of incident AF (n = 279) was analyzed. RESULTS: B/T ratio > median was associated with increased risk of ischemic stroke in study participants without AF (adjusted HR 1.49; 95% CI 1.08-2.06), while an association could not be demonstrated in the presence of AF. Moreover, the B/T ratio was not associated with the risk of AF (HR 0.96; 95% CI 0.75-1.24). CONCLUSIONS: Pro-inflammatory IL6 trans-signaling, estimated by the B/T ratio, is associated with ischemic stroke in individuals without AF. These findings suggest that the B/T ratio could be used to assess the risk of non-AF associated ischemic stroke.

Intake of food rich in saturated fat in relation to subclinical atherosclerosis and potential modulating effects from single genetic variants.

The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54-79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMTmean, C-IMTmax), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMTmean (OR:1.27;1.06-1.47), CC-IMTmean (OR:1.22;1.04-1.44) and ICA-IMTmean (OR:1.26;1.07-1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.

Alcohol consumption in relation to carotid subclinical atherosclerosis and its progression: results from a European longitudinal multicentre study.

BACKGROUND/AIM: The association between alcohol consumption and subclinical atherosclerosis is still unclear. Using data from a European multicentre study, we assess subclinical atherosclerosis and its 30-month progression by carotid intima-media thickness (C-IMT) measurements, and correlate this information with self-reported data on alcohol consumption. METHODS: Between 2002-2004, 1772 men and 1931 women aged 54-79 years with at least three risk factors for cardiovascular disease (CVD) were recruited in Italy, France, Netherlands, Sweden, and Finland. Self-reported alcohol consumption, assessed at baseline, was categorized as follows: none (0 g/d), very-low (0 - 5 g/d), low (> 5 to ≤ 10 g/d), moderate (> 10 to ≤ 20 g/d for women, > 10 to ≤ 30 g/d for men) and high (> 20 g/d for women, > 30 g/d for men). C-IMT was measured in millimeters at baseline and after 30 months. Measurements consisted of the mean and maximum values of the common carotids (CC), internal carotid artery (ICA), and bifurcations (Bif) and whole carotid tree. We used quantile regression to describe the associations between C-IMT measures and alcohol consumption categories, adjusting for sex, age, physical activity, education, smoking, diet, and latitude. RESULTS: Adjusted differences between median C-IMT values in different levels of alcohol consumption (vs. very-low) showed that moderate alcohol consumption was associated with lower C-IMTmax[- 0.17(95%CI - 0.32; - 0.02)], and Bif-IMTmean[- 0.07(95%CI - 0.13; - 0.01)] at baseline and decreasing C-IMTmean[- 0.006 (95%CI - 0.011; - 0.000)], Bif-IMTmean[- 0.016(95%CI - 0.027; - 0.005)], ICA-IMTmean[- 0.009(95% - 0.016; - 0.002)] and ICA-IMTmax[- 0.016(95%: - 0.032; - 0.000)] after 30 months. There was no evidence of departure from linearity in the association between alcohol consumption and C-IMT. CONCLUSION: In this European population at high risk of CVD, findings show an inverse relation between moderate alcohol consumption and carotid subclinical atherosclerosis and its 30-month progression, independently of several potential confounders.

Expression of Interleukin 6 signaling receptors in carotid atherosclerosis.

Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and sGP130-RAPS (sGP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman's correlation. Differences in plasma and gene expression levels between patients with (n = 53) and without (n = 25) a history of a cerebral event and statin-treated (n = 65) and non-treated (n = 11), were estimated by Kruskal-Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without (p = 0.007). Statin-treated had higher IL6R, sIL6R, and sGP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.

Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study.

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study (n = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels (p < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMTmax and c-IMTmean-max (p = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.

A Swedish primary healthcare prevention programme focusing on promotion of physical activity and a healthy lifestyle reduced cardiovascular events and mortality: 22-year follow-up of 5761 study participants and a reference group.

OBJECTIVE: To evaluate long-term risk of first cardiovascular (CV) events, CV deaths and all-cause deaths in community-dwelling participants of a cardiovascular disease (CVD) prevention programme delivered in a primary care setting. METHODS: Individuals who visited a primary healthcare service in Sollentuna (Sweden) and agreed to participate in the programme between 1988 and 1993 were followed. They had at least one CV risk factor but no prior myocardial infarction and received support to increase physical activity using the programme Physical Activity on Prescription and to adopt health-promoting behaviours including cooking classes, weight reduction, smoking cessation and stress management. Participants (n=5761) were compared with a randomly selected, propensity score-matched reference group from the general population in Stockholm County (n=34 556). All individuals were followed in Swedish registers until December 2011. RESULTS: In the intervention group and the reference group there were 698 (12.1%) and 4647 (13.4%) first CV events, 308 (5.3%) and 2261 (6.5%) CV deaths, and 919 (16.5%) and 6405 (18.5%) all-cause deaths, respectively, during a mean follow-up of 22 years. The HR (95% CI) in the intervention group compared with the reference group was 0.88 (0.81 to 0.95) for first CV events, 0.79 (0.70 to 0.89) for CV deaths and 0.83 (0.78 to 0.89) for all-cause deaths. CONCLUSIONS: Participation in a CVD prevention programme in primary healthcare focusing on promotion of physical activity and healthy lifestyle was associated with lower risk of CV events (12%), CV deaths (21%) and all-cause deaths (17%) after two decades. Promoting physical activity and healthy living in the primary healthcare setting may prevent CVD.