Causes of death after first time venous thromboembolism.

BACKGROUND: Causes of death after first time community-acquired venous thromboembolism (VTE) diagnosed in unselected patients at the emergency department (ED) was investigated. MATERIALS AND METHODS: The study consists of all patients > 18 years of age who had a visit for any medical reason to any of 5 different ED in Stockholm County, Sweden from 1st January 2016 to 31st December 2017. We have identified all patients with a first registered incident VTE; deep vein thrombosis (DVT) and/or pulmonary embolism (PE) during the study period. Cox regression models were used to estimate hazards ratios (HR) with 95% confidence intervals (CIs) for all-cause mortality and cause-specific death in patients with DVT or PE using all other patients as the reference group. RESULTS: In total, 359,884 patients had an ED visit during the study period of whom about 2.1% were diagnosed with VTE (DVT = 4,384, PE = 3,212). The patients with VTE were older compared to the control group. During a mean follow up of 2.1 years, 1567 (21%) and 23,741(6.7%) patients died within the VTE and reference group, respectively. The adjusted risk of all-cause mortality was nearly double in patients with DVT (HR 1.7; 95% CI, 1.5-1.8) and more than 3-fold in patients with PE (HR 3.4; 95% CI, 3.1-3.6). While the risk of cancer related death was nearly 3-fold in patient with DVT (HR 2.7; 95% CI, 2.4-3.1), and 5-fold in PE (HR 5.4; 95% CI, 4.9-6.0 respectively). The diagnosis of PE during the ED visit was associated with a significantly higher risk of cardiovascular death (HR 2.2; 95% CI, 1.9-2.6). CONCLUSION: Patients with VTE have an elevated risk of all-cause mortality, including cardiovascular death.

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.

Acute, periprocedural and longterm antithrombotic therapy in older adults: 2022 Update by the ESC Working Group on Thrombosis

The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.

IL-6 signalling biomarkers in hospitalised patients with moderate to severe SARS-CoV-2 infection in a single centre study in Sweden.

BACKGROUND: COVID-19 disease severity and need for intensive care has been associated with profound immune disturbances in which interleukin 6 (IL-6) is central. IL-6 signals through two pathways: classical IL-6 signalling with C-reactive protein (CRP) as a product is pivotal in the acute immune response against pathogens while IL-6 trans-signalling is involved in prolonged inflammation. We measured biomarkers of the IL-6 classical and trans-signalling pathways in patients with moderate or severe COVID-19 in the first wave of the COVID-19 pandemic. METHOD: In a longitudinal cohort study including patients admitted to Danderyd hospital, Stockholm, Sweden, with COVID-19 (n = 112), plasma IL-6 mirroring activity in both pathways, CRP as marker of classical signalling and the soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) as markers of trans-signalling were analysed at baseline. Potential differences in biomarker levels between groups of moderate and severe COVID-19 defined by care level, level of respiratory support and one-month mortality was analysed, as was correlations between biomarkers. In addition, levels 4 months after hospital admission were compared to those at baseline. RESULTS: Levels of IL-6 and CRP were increased in severe COVID-19 whereas IL-6 trans-signalling markers (sIL-6R, sgp130) did not differ between the groups. CRP correlated positively with IL-6 in all patients while correlation with IL-6 could not be demonstrated for sIL-6R and sgp130 in either group. Levels of IL-6, CRP and sIL-6R were significantly decreased after 4 months whereas sgp130 levels increased. CONCLUSION: Classical signalling is the dominating IL-6 pathway in moderate-severe COVID-19.

The DASH diet is associated with a lower risk of heart failure: a cohort study.

AIMS: Trials demonstrate that following the DASH diet lowers blood pressure, which may prevent the development of heart failure (HF). We investigated the association between long-term adherence to the DASH diet and food substitutions within the DASH diet on the risk of HF. METHODS AND RESULTS: Men and women aged 45-83 years without previous HF, ischaemic heart disease or cancer at baseline in 1998 from the Cohort of Swedish Men (n = 41 118) and the Swedish Mammography Cohort (n = 35 004) were studied. The DASH diet emphasizes intake of fruit, vegetables, whole grains, nuts and legumes, and low-fat dairy and deemphasizes red and processed meat, sugar-sweetened beverages, and sodium. DASH diet scores were calculated based on diet assessed by food frequency questionnaires in late 1997 and 2009. Incidence of HF was ascertained using the Swedish Patient Register. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). During the median 22 years of follow-up (1998-2019), 12 164 participants developed HF. Those with the greatest adherence to the DASH diet had a lower risk of HF compared to those with the lowest adherence (HR 0.85, 95% CI: 0.80, 0.91 for baseline diet and HR 0.83, 95% CI: 0.78, 0.89 for long-term diet, comparing quintiles). Replacing 1 serving/day of red and processed meat with emphasized DASH diet foods was associated with an 8-12% lower risk of HF. CONCLUSION: Long-term adherence to the DASH diet and relevant food substitutions within the DASH diet were associated with a lower risk of HF.

Interleukin 6 trans-signalling and the risk of future cardiovascular events in men and women.

OBJECTIVE: Pro-inflammatory interleukin 6 (IL6) trans-signalling is associated with increased risk of cardiovascular events (CVEs). Whether this association exists for both sexes is, however, uncertain. Hence, we analysed the risk of CVE associated with IL6 trans-signalling in men and women and investigated if potential interaction between IL6 trans-signalling and sex affects the risk. METHODS: In a prospective cohort of 60-year-old men and women without cardiovascular disease (men=2039, women=2193), subjects were followed for 20 years. To assess the IL6 trans-signalling activity, the proportion between the active binary and inactive ternary IL6 complexes, the binary/ternary ratio (B/T ratio), was estimated. CVE (myocardial infarction, angina pectoris and ischaemic stroke, n=629) risk was analysed with Cox regression, presented as HRs with 95% CIs. B/T ratio was dichotomised, with levels >median representing IL6 trans-signalling. Interaction was analysed on the additive scale and expressed as the synergy index (S). Analyses were adjusted for cardiovascular risk factors. RESULTS: B/T ratio >median was associated with increased CVE risk in men (HR 1.63; 95% CI 1.32 to 2.01), but not in women (HR 1.21; 95% CI 0.93 to 1.57). There was a significant synergistic interaction (S=1.98; 95% CI 1.15 to 3.42) between the B/T ratio and male sex, the combination increasing the risk by 88%. CONCLUSIONS: Our results suggest differential susceptibility to inflammation mediated by IL6 trans-signalling and subsequent CVE in men and women. The B/T ratio could be considered as a novel biomarker for cardiovascular risk in men, but not in women.

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.

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.

Risk of Ischemic Stroke and Major Bleeding in Patients with Atrial Fibrillation and Cancer.

BACKGROUND: Atrial fibrillation (AF) is an important risk factor for ischemic stroke. Cancer may increase the risk both of ischemic stroke and of bleeding. Less is known about risk of ischemic stroke and bleeding among cancer patients with AF, complicating the prevention of ischemic stroke in these patients. METHODS: Register based cohort study comprising all Swedish patients hospitalized with a primary diagnosis of AF from July 1, 2005 until December 31, 2014. Patients with cancer diagnosis were compared to the rest of the cohort. We repeated the analysis focusing on recent cancer diagnosis and on cancer types prone to thromboembolism. Associations between predictor and outcome variables were analyzed with Cox regression. RESULTS: The cohort consisted of 294,989 AF patients including 71,882 with prior cancer diagnosis. After adjustments, neither cancer diagnosis overall, recent cancer diagnosis, or any subgroup of cancer were associated with increased risk of ischemic stroke. Several cancer forms were however associated with risk of major bleedings, including risk of intracranial hemorrhage for patients with prostate cancer and risk of gastrointestinal bleeds for patients with colorectal and pancreatic cancer, adjusted hazard ratios with 95% confidence intervals 1.31 (1.06-1.62), 1.74 (1.53-1.97), and 2.86 (1.80-4.55) respectively. CONCLUSION: Cancer diagnosis was not associated with increased risk of ischemic stroke but several cancer forms were associated with risk of major bleedings in this large, Swedish cohort of AF patients. The results may have implications for prevention of ischemic stroke in these patients.

Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study.

The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10-5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (ß = 0.03 SE = 0.007, p = 4.77 × 10-5) and inversely associated with c-IMT (c-IMTmean-max ß = -0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.

The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events.

BACKGROUND: Interleukin 6 trans-signalling is independently associated with the risk of cardiovascular events. The aim of this study was to investigate if interleukin 6 trans-signalling can identify individuals at risk for cardiovascular events (coronary artery disease and ischaemic stroke) among those at-low-intermediate risk. METHODS: In a cohort of 60-year-olds (n = 4232, incident cardiovascular events n = 525), interleukin 6 trans-signalling was estimated by a ratio between the pro-inflammatory interleukin 6: soluble interleukin 6 receptor binary receptor complex and the inactivated interleukin 6: soluble interleukin 6 receptor: sgp130 ternary complex (B/T ratio). Risk associated with B/T ratio >median was investigated in individuals with low-density lipoprotein cholesterol ≤4.0 (mmol/l) and in those at low-intermediate risk according to the Framingham risk score (FRS) using Cox regression and expressed as hazard ratio and 95% confidence interval. Difference in time to event (years; 95% confidence interval) was analysed with quantile regression. The interaction between low-density lipoprotein cholesterol and B/T ratio was estimated on the additive scale. Incremental discriminatory value of the B/T ratio if low-density lipoprotein cholesterol ≤4.0 was compared to that of the FRS and interleukin 6. RESULTS: B/T ratio >median was associated with increased cardiovascular event risk when low-density lipoprotein cholesterol ≤4.0 (hazard ratio 1.59; 95% confidence interval 1.24-2.05) or FRS ≤ 10%, >10-≤20% (hazard ratio 1.27; 95% confidence interval 1.00-1.61 and hazard ratio 1.78; 95% confidence interval 1.36-2.34, respectively). B/T ratio >median and low-density lipoprotein cholesterol ≤4.0 were associated with early cardiovascular events, particularly ischaemic stroke. No interaction was observed between low-density lipoprotein cholesterol and the B/T ratio, both factors increasing cardiovascular event risk by 60%. In the presence of low-density lipoprotein cholesterol ≤4.0, the B/T ratio slightly improved discrimination measures. CONCLUSIONS: Interleukin 6 trans-signalling increases cardiovascular event risk in middle-aged men and women otherwise classified at low-intermediate cardiovascular risk.

Serum IL8 is not associated with cardiovascular events but with all-cause mortality.

BACKGROUND: The aim of this study is to investigate if IL8 levels were associated with incident cardiovascular (CV) events (CVE) and mortality (all-cause, CV, and cancer) in a cohort of 60 years old men and women from Stockholm (60YO). METHODS: The 60YO comprises 4232 participants; baseline period: 1997-1999. The cohort is matched annually to population registries to record deaths and incident CVE. Serum IL8 was measured in 4011 participants and categorized in quartiles. Cox proportional hazard models were used to estimate the CVE and mortality risk, expressed as hazard ratios (HR) with 95% confidence intervals (CI). Potential confounding was addressed by adjusting for traditional CV risk factors (CVE estimates) and by sex, life style habits, metabolic factors (mortality estimates). Laplace regression was used to calculate the difference in time until a certain percentage of the cohort died according to IL8 levels. RESULTS: During 16.5 years follow up, 522 incident CVE were recorded and 647 study participants died. IL8 was not associated with CVE risk (IL8 Q4 vs Q1, HR of 0.95; 95% CI 0.75-1.22). Compared to Q1, IL8 Q4 was associated with all-cause mortality (adjusted HR 1.28; 95% CI 1.02-1.63). No association was observed with CV and cancer related mortality in the fully adjusted model. Participants with IL8 above the median died of any cause ≈1.3 years before the 15% of the population had died. CONCLUSION: Elevated IL8 levels were not associated with CVE risk and CV mortality, but were associated with an increased risk of all-cause mortality regardless of the underlying cause.

Interleukin 6 trans-signalling and risk of future cardiovascular events.

Aims: The pro-inflammatory response to interleukin 6 (IL6) trans-signalling in atherosclerosis is driven by the IL6 and soluble IL6 receptor (sIL6R) binary complex. The binary IL6:sIL6R complex is inactivated by sgp130 through the formation of the ternary IL6:sIL6R:sgp130 complex. The aim of this study was to investigate if IL6 trans-signalling, estimated by a ratio between the binary and ternary complexes, associates with the risk of future cardiovascular events (CVE) in a Swedish cohort of 60-year-old men and women (n = 4232). Methods and results: Binary and ternary complex levels expressed in nanomol/Litre were derived from serum concentrations of IL6, sIL6R, and sgp130. Cox regression models were used to assess the risk of CVE (myocardial infarction, angina pectoris, and ischaemic stroke, n = 525), expressed as hazard ratio (HR) with 95% confidence interval (CI), associated with increasing circulating levels of the three molecules and with the binary/ternary complex ratio. Estimates were adjusted for the common cardiovascular (CV) risk factors. To assess the level of IL6-trans-signalling, we estimated the binary/ternary complex ratio and then analysed the association with CVE risk. A ratio higher than the median, representing a relative excess of the active binary complex was associated with increased CVE risk (adjusted HR 1.44, 95% CI 1.21-1.72). Conclusion: The ratio between the functional moieties of IL6 trans-signalling, IL6:sIL6R, and IL6:sIL6R:sgp130, was associated with CVE risk indicating that it could be a promising marker of CV risk and possibly be used in selecting patients for anti-inflammatory therapy.

Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data.

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( Ptrend < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were -5.0, -2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( Ptrend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.

Effects of Angiotensin-Converting Enzyme Inhibition and Alpha 1-Adrenergic Receptor Blockade on Inflammation and Hemostasis in Human Hypertension.

Drugs blocking the renin-angiotensin-aldosterone system may offer benefit on endothelial function, inflammation, and hemostasis in addition to the effects of reducing blood pressure. We examined the contribution of the angiotensin-converting enzyme inhibitor ramipril and the alpha 1-adrenergic receptor blocker doxazosin on blood pressure and on markers of inflammation and hemostasis in 59 individuals with mild-to-moderate hypertension randomized to receive double-blind ramipril 10 mg od or doxazosin 8 mg od for 12 weeks. Inflammatory markers (interleukin-6, soluble interleukin-6 receptor, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and C-reactive protein) and hemostasis (plasminogen activator inhibitor-1 activity, tissue plasminogen activator antigen, thrombin-antithrombin complex, and thrombin generation by calibrated automated thrombogram) were assessed. The treatment reduced blood pressure in both groups. Thrombin-antithrombin complex decreased by treatment, and this was dependent on a reduction in thrombin-antithrombin complex in the ramipril group alone. There were no changes in plasminogen activator inhibitor-1 activity, whereas tissue plasminogen activator antigen increased by ramipril and decreased by doxazosin. Only minor changes were observed in systemic inflammation by treatment. Treatment with ramipril seems to reduce thrombin generation beyond effects on reducing blood pressure. Drugs blocking the renin-angiotensin-aldosterone system may reduce atherothrombotic complications beyond their effects to reduce blood pressure.

Comorbidities in relation to fatality of first myocardial infarction.

INTRODUCTION: Present knowledge concerning potential associations between comorbidities and the fatality of a first myocardial infarction (MI) is limited. AIM: To identify comorbidities in 45-70-year-old individuals who suffered a first MI and died within 7 days in Stockholm County from 1992-1994. In addition, to assess how each of the comorbidities identified, as well as the number of hospitalizations during the 10-year period prior to the MI, was associated with MI fatality. METHODS: The data collected on our inception cohort of 1984 first MI, of which 524 were fatal within 7 days, were primarily self-reported, proxy-reported by questionnaire and/or extracted from comprehensive national registers. Comorbidities among fatal cases with a prevalence >2% were identified. Risk ratios (with 95% confidence intervals) for the association of MI fatality with number of prior hospitalizations and specific comorbidities were calculated using binomial regression with log link. A structured review of autopsy reports on fatal cases was performed in order to identify additional indicators of comorbidities. RESULTS: After adjusting for sex, age and disposable income, the number of previous hospitalizations was associated with 7-day MI fatality. Of the comorbidities identified as prevalent in fatal cases, the following were associated with 7-day fatality in crude analysis: epilepsy, heart failure, stroke, alcoholism, cancer, renal diseases, asthma, psychiatric diseases, diabetes, and rheumatoid arthritis. Indicators of comorbidities identified from autopsy data included a silent MI, severe atherosclerosis of the abdominal aorta, and hepatic steatosis. Adjustments for sex and age (although not possible for epilepsy and alcoholism), did not substantially alter results. CONCLUSIONS: Our current findings indicate that in connection with a first MI, particular attention should be paid to those with repeated prior hospitalizations and/or epilepsy, heart failure, stroke, alcoholism, cancer, renal diseases, asthma, psychiatric diseases, diabetes and rheumatoid arthritis.

Exposure to Traffic-Related Air Pollution and Serum Inflammatory Cytokines in Children.

BACKGROUND: Long-term exposure to ambient air pollution can lead to adverse health effects in children; however, underlying biological mechanisms are not fully understood. OBJECTIVES: We evaluated the effect of air pollution exposure during different time periods on mRNA expression as well as circulating levels of inflammatory cytokines in children. METHODS: We measured a panel of 10 inflammatory markers in peripheral blood samples from 670 8-y-old children in the Barn/Child, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) birth cohort. Outdoor concentrations of nitrogen dioxide (NO2) and particulate matter (PM) with aerodynamic diameter <10 µm (PM10) from road traffic were estimated for residential, daycare, and school addresses using dispersion modeling. Time-weighted average exposures during infancy and at biosampling were linked to serum cytokine levels using linear regression analysis. Furthermore, gene expression data from 16-year-olds in BAMSE (n=238) were used to evaluate links between air pollution exposure and expression of genes coding for the studied inflammatory markers. RESULTS: A 10 µg/m3 increase of NO2 exposure during infancy was associated with a 13.6% (95% confidence interval (CI): 0.8; 28.1%) increase in interleukin-6 (IL-6) levels, as well as with a 27.8% (95% CI: 4.6, 56.2%) increase in IL-10 levels, the latter limited to children with asthma. However, no clear associations were observed for current exposure. Results were similar using PM10, which showed a high correlation with NO2. The functional analysis identified several differentially expressed genes in response to air pollution exposure during infancy, including IL10, IL13, and TNF;. CONCLUSION: Our results indicate alterations in systemic inflammatory markers in 8-y-old children in relation to early-life exposure to traffic-related air pollution. https://doi.org/10.1289/EHP460.

IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds.

OBJECTIVE: Phosphatidylserine is exposed on apoptotic cells and is prone to oxidation (OxPS). Here we analyze the association of IgM antibodies against OxPS (anti-OxPS) with the risk of cardiovascular disease (CVD). METHODS: Among sixty-year olds from Stockholm County in Sweden, previously screened for cardiovascular risk factors (2039 men, 2193 women), there were 210 incident CVD-cases identified during a 5-year follow-up. Using a nested case-control design, 622 age- and sex-matched controls were selected. Odds ratios (OR) with 95% intervals (CI) were calculated by conditional logistic regression. IgM anti-OxPS was measured by ELISA. Phagocytosis of apoptotic Jurkat-cells by macrophages was studied by flow cytometry. RESULTS: Anti-OxPS levels were lower among cases (median (interquartile range): 80.7 (60.9-101.0 vs. 84.6 (65.8-109.6); p = 0.047); among men (76.6 (55.8-99.2) vs. 82.0 (63.1-105.1); p = 0.022) and among women 89.6 (72.3-110.1) vs. 89.8 (69.9-114.4); p = 0.79). After adjustment for smoking, BMI, diabetes mellitus type II, hypercholesterolaemia and hypertension, and dividing into quartiles, using the highest quartile (quartile 4) as reference, quartile 3 was associated with a OR of 1.74 (CI 1.08-2.81). Quartiles 2 and 1 had similar associations, the later reaching statistical significance. Among men associations were stronger whereas no significant associations were observed in women. The OR of MI/angina comparing quartile 3 with quartile 4 was 2.31 (CI 1.30-4.11). The OR for quartile 2 and 1, respectively, were similar as for quartile 3. Total IgM increased uptake of apoptotic cells, which was reversed if incubated with OxPS. CONCLUSIONS: IgM anti-OxPS is a novel potential protection marker for CVD, in particular in men. Increased phagocytosis of dying/dead cells could be one potential underlying mechanism.

Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60-Year-Olds.

BACKGROUND: Malondialdehyde (MDA) is generated during lipid peroxidation as in oxidized low-density lipoprotein, but antibodies against oxidized low-density lipoprotein show variable results in clinical studies. We therefore studied the risk of cardiovascular disease (CVD) associated with IgM antibodies against MDA conjugated with human albumin (anti-MDA). METHODS AND RESULTS: In a 5- to 7-year follow-up of 60-year-old men and women from Stockholm County previously screened for cardiovascular risk factors (2039 men, 2193 women), 209 incident CVD cases (defined as new events of coronary heart disease, fatal and nonfatal myocardial infarction, ischemic stroke, and hospitalization for angina pectoris) and 620 age- and sex-matched controls were tested for IgM anti-MDA by ELISA. Antibody peptide/protein characterization was done using a proteomics de novo sequencing approach. After adjustment for smoking, body-mass index, type 2 diabetes mellitus, hyperlipidemia, and hypertension, an increased CVD risk was observed in the low IgM anti-MDA percentiles (below 10th and 25th) (odds ratio and 95% CI: 2.0; 1.19-3.36 and 1.67; 1.16-2.41, respectively). Anti-MDA above the 66th percentile was associated with a decreased CVD risk (odds ratio 0.68; CI: 0.48-0.98). After stratification by sex, associations were only present among men. IgM anti-MDA levels were lower among cases (median [interquartile range]: 141.0 [112.7-164.3] versus 147.4 [123.5-169.6]; P=0.0177), even more so among men (130.6 [107.7-155.3] versus 143.0 [120.1-165.2]; P=0.001). The IgM anti-MDA variable region profiles are distinctly different and also more homologous in their content (correlates strongly with fewer peptides) than control antibodies (not binding MDA). CONCLUSIONS: IgM anti-MDA is a protection marker for CVD. This finding could have diagnostic and therapeutic implications.