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Background In acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into circulation and contribute to inflammation and adverse cardiac remodelling. We aimed to investigate gut leakage markers and their associations with inflammation, infarct size and cardiac function.Methods We examined 61 ST-elevation myocardial infarction (STEMI) patients who developed acute HF within 48 hours of successful percutaneous coronary intervention (PCI). Serial blood samples were taken to measure lipopolysaccharide (LPS), LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14) and intestinal fatty acid binding protein (I-FABP). Cumulative areas under the curve (AUCs) from baseline to day 5 were calculated. Serial echocardiography was performed to assess left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and wall motion score index (WMSI). Single-photon emission CT (SPECT) was performed at 6 weeks to determine infarct size and LVEF.Results I-FABPAUC correlated positively with infarct size (rs=0.45, p=0.002), GLS (rs=0.32, p=0.035) and WMSI (rs=0.45, p=0.002) and negatively with LVEF measured by SPECT (rs=−0.40, p=0.007) and echocardiography (rs=−0.33, p=0.021) at 6 weeks. LPSAUC, LBPAUC and sCD14AUC did not correlate to any cardiac function marker or infarct size. Patients, who at 6 weeks had above median GLS and WMSI, and below-median LVEF measured by SPECT, were more likely to have above median I-FABPAUC during admission (adjusted OR (aOR) 5.22, 95% CI 1.21 to 22.44; aOR 5.05, 95% CI 1.25 to 20.43; aOR 5.67, 95% CI 1.42 to 22.59, respectively). The same was observed for patients in the lowest quartile of LVEF measured by echocardiography (aOR 9.99, 95% CI 1.79 to 55.83) and three upper quartiles of infarct size (aOR 20.34, 95% CI 1.56 to 264.65).Conclusions In primary PCI-treated STEMI patients with acute HF, I-FABP, a marker of intestinal epithelial damage, was associated with larger infarct size and worse cardiac function after 6 weeks.

Background: Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect. Objectives: The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI. Methods: In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI). Results: All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P

Background: Non-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation. Methods: In this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies.

Abstract Background Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. Methods We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. Results Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. Conclusions Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis. Trial registration NCT02637167, registered December 22, 2015.

Abstract Background Inflammation in cardiac adipose tissue (AT) is associated with atherosclerosis. We investigated whether the epicardial-, pericardial and pre-sternal subcutaneous AT (EAT, PAT and SAT) expression of Sirtuin1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) are involved in the inflammatory process in coronary heart disease (CHD), and potentially associated to nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related markers, macrophage polarization markers, cell markers and the cardiometabolic profile. Methods In this cohort study performed between 2016 and 2018, EAT, PAT and SAT biopsies were retrieved from 52 CHD patients (77% men, median age 67) undergoing open-chest coronary artery bypass grafting (CABG), and 22 patients (50% men, median age 69) undergoing aortic valve replacement serving as controls. AT samples were snap-frozen at – 80 °C until RNA extraction and AT expression of actual markers, relatively quantified by PCR. Circulating SIRT1 and NAMPT were measured with Enzyme-linked immunosorbent assays (ELISAs). Non-parametric statistical tests were mainly used, including Friedman’s test coupled to Wilcoxon signed-rank test and Spearman Correlation. Results SIRT1 and NAMPT levels were similar in CHD and controls. In CHD, SIRT1 and NAMPT were inter-correlated in all AT compartments (r = 0.37–0.56, p

Introduction: Biomarkers of inflammation and brain damage are associated with neurodegeneration and dementia but are scarcely investigated post-stroke. We hypothesized that biomarkers of brain tissue damage and inflammation are associated with i) cognition and imaging markers of brain pathology seven years post-stroke and ii) long-term cognitive deterioration post-stroke. Methods: All patients with a first-ever stroke or TIA admitted to the stroke unit, Bærum Hospital, Norway, during 2007/2008 were invited to participate in the CAST (Cognition After Stroke) study and invited to a follow-up after one and seven years with cognitive assessments and diagnoses of dementia, mild cognitive impairment (MCI) or normal. After seven years, we measured serum glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), Interleukin (IL) 8, 12, 18, and high sensitive C-reactive protein (hsCRP) and brain MRI for assessment of Fazekas and global cortical and medial temporal lobe atrophy (MTA). Results: Of 227 subjects recruited, 116 completed the seven-year follow-up, 113 with blood biomarkers, and were included in this study. Of these, 77 had complete MRI examinations. Mean age at baseline was 67.9 (SD 11.0) years, 87 (77 %) suffered an ischemic stroke, and 52 (46%) were women. The mean age after seven years was 75.4 (SD 11.1). At one- and seven-years follow-up, 62 (55%) and 45 (40%) had normal cognition, 37 (33%) and 42 (37 %) MCI, while 14 (12 %) and 26 (23%) had dementia, respectively. Cognitively, 35 patients progressed during follow-up. In unadjusted logistic regression, only hsCRP was associated with post-stroke dementia (odds ratio 1.08, 95% confidence interval 1.02 to 1.14, p=0.01). Adjusting for age did not change the result (OR 1.09, 95% confidence interval 1.06-1.19, p

Background Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size.Methods STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24–36, 72–168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months.Results Repeated measures analysis of variance showed significant (p

BackgroundThe gut microbiota in patients with chronic heart failure (HF) is characterized by low bacterial diversity and reduced ability to synthesize beneficial metabolites. These changes may facilitate leakage of whole bacteria or bacterial products from the gut into the bloodstream, which may activate the innate immune system and contribute to the low-grade inflammation seen in HF. In this exploratory cross-sectional study, we aimed to investigate relationships between gut microbiota diversity, markers of gut barrier dysfunction, inflammatory markers, and cardiac function in chronic HF patients.MethodsIn total, 151 adult patients with stable HF and left ventricular ejection fraction (LVEF) 895 pg/ml) had increased I-FABP (p

BackgroundEpicardial and pericardial adipose tissue (EAT and PAT) surround and protect the heart, with EAT directly sharing the microcirculation with the myocardium, possibly presenting a distinct macrophage phenotype that might affect the inflammatory environment in coronary heart disease (CHD). This study aims to investigate the expression of genes in different AT compartments driving the polarization of AT macrophages toward an anti-inflammatory (L-Galectin 9; CD206) or pro-inflammatory (NOS2) phenotype.MethodsEAT, PAT, and subcutaneous (SAT) biopsies were collected from 52 CHD patients undergoing coronary artery bypass grafting, and from 22 CTRLs undergoing aortic valve replacement. L-Galectin9 (L-Gal9), CD206, and NOS2 AT gene expression and circulating levels were analyzed through RT-PCR and ELISA, respectively.ResultsL-Gal9, CD206, and NOS2 gene expression was similar in all AT compartments in CHD and CTRLs, as were also L-Gal9 and CD206 circulating levels, while NOS2 serum levels were higher in CHD (p = 0.012 vs. CTRLs). In CTRLs, NOS2 expression was lower in EAT vs. SAT (p = 0.007), while in CHD patients CD206 expression was lower in both SAT and EAT as compared to PAT (p = 0.003, p = 0.006, respectively), suggestive of a possible macrophage reprogramming toward a pro-inflammatory phenotype in EAT. In CHD patients, NOS2 expression in SAT correlated to that in PAT and EAT (p = 0.007, both), CD206 expression correlated positively to L-Gal9 (p

Abstract Background The fibrinolytic system plays an important role in coronary artery atherothrombosis, and especially circulating plasminogen-activator inhibitor (PAI) type 1 (PAI-1) associates with increased mortality, infarct size and heart failure in patients with myocardial infarction (MI). In a cross-sectional study, we aimed to study whether genes encoding tissue plasminogen activator (tPA), urinary-type plasminogen activator (uPA), PAI-1 and PAI-2 are expressed in coronary thrombi from acute ST-elevation MI (STEMI) patients. Any relations to myocardial injury measured by peak troponin T, time from symptom onset to Percutaneous Coronary Intervention (PCI), and to different cell types present in the thrombi were also explored. Methods Intracoronary thrombi were aspirated from 33 STEMI patients treated with primary PCI. The thrombi were snap-frozen for gene expression analyses, relatively quantified by RT PCR. Peripheral blood samples were drawn. Correlations were performed by Spearmans rho. Results The genes were present in 74–94% of the thrombi. Median peak troponin T was 3434 μ/L and median ischemic time 152 min. There were no significant correlations between the measured genes and troponin T, or ischemic time. Genes encoding tPA, u-PA, PAI-1 and PAI-2 all correlated significantly to the presence of monocytes/macrophages (CD68) in the thrombi (p = 0.028, p

Background and aims: Epicardial and pericardial adipose tissue (EAT and PAT) associate with atherosclerosis, however, discussed to have different inflammatory properties. We examined the NLRP3 inflammasome related pathway, playing a pivotal role in atherosclerosis, in EAT, PAT and subcutaneous AT (SAT), their relationship to cell types and anthropometric measures in patients undergoing coronary artery bypass grafting. Methods: Biopsies from EAT, PAT and SAT were collected from 52 patients with coronary heart disease (CHD) (median body weight 85.0 kg) and 22 controls. RNA was extracted and expression of interleukin (IL)-1β, IL-18, NLRP3, Caspase-1, toll-like receptor 4 (TLR4), IL-6, IL-6 receptor and gp130 were analyzed by RT-PCR. Results: Limited differences in any genes between CHD patients and controls. IL-18 and IL-6 were 4-fold higher expressed in EAT versus PAT (p

Introduction ADAMTS13 cleaves von Willebrand factor (VWF) multimers into less active fragments. Both markers have been related to cardiovascular disease (CVD). We aimed to investigate the influence of ADAMTS13 single nucleotide polymorphisms (SNPs) on levels of ADAMTS13 and VWF, and CVD. Methods The c.1342C>G, g.41635A>G and c.2699C>T polymorphisms were determined in patients with chronic coronary syndrome (n = 1000). VWF and ADAMTS13 were analyzed. Clinical endpoints after 2 years (n = 106) were unstable angina pectoris, myocardial infarction, non-hemorrhagic stroke and death. Results The SNPs did not affect ADAMTS13 levels. The 41635A-allele associated with higher VWF levels ( P

Introduction: The complement system and neutrophil extracellular traps (NETs) might contribute to ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI). We aimed to estimate associations between complement activation and NETs in STEMI, and their prognostic value on clinical endpoints. Methods: In this cohort study, 864 patients admitted for PCI during STEMI were included. Complement activation was analyzed by the terminal complement complex (TCC), while NETs were analyzed by myeloperoxidase-DNA, citrullinated histone 3 (CitH3) and dsDNA. The composite endpoint was reinfarction, unscheduled revascularization, stroke, hospitalization due to heart failure, or death, and the secondary endpoint was total mortality. The association between TCC and clinical endpoints was assessed by Cox regression and ROC curve analysis. Results: TCC was weakly correlated to dsDNA (r = 0.127, p

Abstract Aims/Introduction The shortening of leukocyte telomere length with age has been associated with coronary disease, whereas the association with type 1 diabetes is unclear. We aimed to explore telomere lengths in diabetes patients with regard to coronary artery disease, compared with healthy controls. The longevity factors sirtuin 1 and growth‐differentiating factor 11 were investigated accordingly. Materials and Methods We carried out a cross‐sectional study of 102 participants with long‐term type 1 diabetes and 75 controls (mean age 62 and 63 years, respectively), where 88 cases and 60 controls without diagnosed coronary artery disease completed computed tomography coronary angiography. Telomere lengths and gene expression of sirtuin 1 and growth‐differentiating factor 11 were quantified in leukocytes. Results Telomere lengths and sirtuin 1 were reduced in diabetes patients versus controls, medians (25th to 75th percentiles): 0.97 (0.82–1.15) versus 1.08 (0.85–1.29) and 0.88 (0.65–1.14) vs 1.01 (0.78–1.36), respectively, adjusted P 50% stenosis, was not associated with the investigated variables. Conclusions Long‐term type 1 diabetes presented with reduced telomeres and sirtuin 1 expression, with additional reduction in diabetes patients with previous coronary artery disease, showing their importance for cardiovascular disease development with potential as novel biomarkers in diabetes and coronary artery disease.

Abstract Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT. ClinicalTrials.gov (NCT01181076).

IntroductionAdipokines are highly active biopeptides involved in glucose metabolism, insulin regulation and the development and progression of obesity and its associated diseases. It includes, among others, adiponectin, visfatin and tumor necrosis factor alpha (TNFα). The sources of adipokines and their associations with glucometabolic variables are not completely understood.AimIn this cross-sectional study, we aimed to investigate whether gene expression levels in subcutaneous adipose tissue (SAT) of selected adipokines and their corresponding circulating levels associate with the amount of AT in superficial (sSAT), deep (dSAT) and visceral AT (VAT), assessed by computed tomography (CT). Any association with glucometabolic variables were also explored.MethodsIn 103 healthy Caucasian men, aged 39.5 years, fasting venous blood and SAT samples from the gluteal region were collected. Ninety-four of the participants underwent CT assessment of the abdominal AT, which was divided into VAT, sSAT and dSAT. Circulating levels of adipokines were measured by ELISA and AT gene-expression by PCR. Insulin sensitivity was determined by glucose clamp, assessing glucose disposal rate (GDR).ResultsCirculating adiponectin and TNFα gene expression correlated inversely and positively to the amount of AT in all three compartments (r=-0.266 to -0.276, p

Summary: Background: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. Methods: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). Findings: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. Interpretation: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. Funding: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

Abstract Aim Gut leakage has been shown to associate with low-grade inflammation and lower cardiorespiratory fitness in diabetic subjects. We aimed to investigate whether gut leakage markers related to cardiorespiratory fitness in patients with both coronary artery disease and type 2 diabetes, and whether these were affected by long-term exercise training. Methods Patients with angiographically verified coronary artery disease and type 2 diabetes mellitus (n = 137) were randomized to either 12 months exercise intervention or conventional follow-up. A cardiopulmonary exercise test and fasting blood samples were obtained before and after intervention to assess VO2peak and the biomarkers soluble CD14, lipopolysaccharide-binding protein and intestinal fatty-acid binding protein as markers of gut leakage. Results 114 patients completed the intervention satisfactory. VO2peak correlated inversely to sCD14 (r = − 0.248, p = 0.004) at baseline. Dividing sCD14 into quartiles (Q), VO2peak was significantly higher in Q1 vs. Q2–4 (p = 0.001), and patients in Q2-4 (sCD14 > 1300 ng/mL) had an OR of 2.9 (95% CI 1.2–7.0) of having VO2peak below median ( 0.05) after 12 months. Conclusions Cardiorespiratory fitness related inversely to sCD14, suggesting physical capacity to be associated with gut leakage in patients with CAD and T2DM. Long-term exercise training did not affect circulating gut leakage markers in our population. Trial registration NCT01232608, Registered 02 November 2010—Retrospectively registered at https://clinicaltrials.gov/ct2/show/NCT01232608?term=NCT01232608&draw=2&rank=1

Total bilirubin consists of an unconjugated form, solubilized by its binding to albumin, and a conjugated form representing a minor part of the circulating bilirubin. As total bilirubin in physiological concentrations is a powerful antioxidant, its concentration gradient may reflect the health status of an individual, and serve as a prognostic indicator of outcome in primary and secondary cardiovascular disease prevention. The aim of this study was to assess the association between total bilirubin and incident cardiovascular events following a myocardial infarction. Total bilirubin in serum was measured at baseline 2–8 weeks after hospitalization for an MI in 881 patients, aged 70 to 82 years, included in the OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) study, where patients were followed-up for up to 2 years. The first major adverse clinical event (MACE) was the primary endpoint and consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. As total bilirubin was non-normally distributed, log-transformed values and quartiles of bilirubin were analyzed using Cox regression models. The median (Q1, and Q3) baseline concentration of bilirubin was 11 (9, and 14) µmol/L, and higher log-transformed concentrations were associated with male sex, lower New York Heart Association (NYHA) class and non-smoking. MACE occurred in 177 (20.1%) patients during the follow-up. Higher concentrations of bilirubin were associated with a lower risk of MACE: HR 0.67 (95%CI 0.47–0.97) per log-unit increase, p = 0.032. Patients in the lowest quartile of bilirubin (p = 0.002, compared to quartiles 2–4. This association remained significant even after adjusting for age, sex, body mass index (BMI), smoking status, NYHA class and treatment allocation: HR 1.52 (1.21–2.09), p = 0.009. Low concentrations of bilirubin (

Background: Selenium and coenzyme Q10 (SeQ10) possess antioxidant and anti-inflammatory properties, potentially mediated via Sirtuin1 (SIRT1). We aimed to investigate the influence of a SeQ10 intervention on SIRT1 concentration, with potential interactions with microRNAs. Methods: In this sub-study of a prospective double-blind placebo-controlled clinical trial, healthy subjects (mean age 76 years) were randomized to receive an active treatment (n = 165, combined 200 µg/day of Se and 200 mg/day of Q10) or a placebo (n = 161). SIRT1 concentration and microRNAs were measured with ELISA and PCR, respectively. Results: After four years, SIRT1 concentration was increased in the active treatment group, with mean (SD) ng/mL of 469 (436) vs. 252 (162), p < 0.001, and decreased in the placebo group, 190 (186) vs. 269 (172), p = 0.002, and the differences between the groups were significant (p = 0.006, adjusted). Those who suffered CV death during a 10-year follow-up (n = 25 and n = 52 in the active treatment and placebo groups, respectively) had significantly lower baseline SIRT1 concentrations compared to the survivors (p < 0.001). MiR-130a-3p was significantly downregulated during the intervention and correlated inversely with SIRT1 at baseline (r = −0.466, p = 0.007). Conclusion: The increased SIRT1 concentration after the SeQ10 intervention associated with reduced CV mortality, partly mediated via miR-1303a-3p, suggests that SIRT1 is an additional mediator of the intervention, preventing vascular ageing.

Introduction: Adipokines, expressed by adipose tissue (AT), have been associated with metabolic disturbances and coronary artery disease (CAD). The impact of exercise training on the AT in patients suffering from both diabetes and CAD is unknown. To gain knowledge on changes in ATs’ inflammatory profile in such a population, we investigated the effects of long-term exercise on selected adipokines and their associations with physical performance and glucometabolic variables. Adiponectin was selected based on its anti-atherogenic and anti-diabetic properties and visfatin and tumour necrosis factor (TNF) for their association with atherosclerosis and metabolic disorders. Not many studies have focused on the effects of long-term exercise training on adipokines in patients with concomitant T2DM and CAD. Methods: Patients with type 2 diabetes and CAD (n = 137), 41–81 years, 17.2% females, were randomized in a 1:1 manner to an exercise group, who underwent 1 year of 150 min weekly combined strength and endurance exercise, or a control group. AT from the gluteal region and blood samples were obtained at baseline and after 12 months, along with a physical performance test, assessed by the VO2 peak. Circulating protein levels were measured by ELISA. RNA was extracted from AT and expression levels were relatively quantified by PCR. Results: After 1 year, no significant difference in the change in the investigated markers between the intervention group and the control group was observed. Changes in circulating adiponectin and VO2 peak correlated in the total population (r = 0.256, p = 0.008). At baseline, circulating adiponectin and TNF correlated inversely with insulin and with C-peptide and VO2peak, respectively (p

Abstract Aims Recent reports have suggested that patients with heart failure (HF) have an altered gut microbiota composition; however, associations with diet remain largely uninvestigated. We aimed to explore differences in the gut microbiota between patients with HF with reduced ejection fraction and healthy controls, focusing on associations with diet and disease severity. Methods and results The microbiota composition of two cross‐sectional cohorts (discovery, n = 40 and validation, n = 44) of patients with systolic HF and healthy controls (n = 266) was characterized by sequencing of the bacterial 16S rRNA gene. The overall microbial community (beta diversity) differed between patients with HF and healthy controls in both cohorts (P < 0.05). Patients with HF had shifts in the major bacterial phyla, resulting in a lower Firmicutes/Bacteroidetes (F/B) ratio than controls (P = 0.005). Patients reaching a clinical endpoint (listing for heart transplant or death) had lower bacterial richness and lower F/B ratio than controls (P < 0.01). Circulating levels of trimethylamine‐N‐oxide were associated with meat intake (P = 0.016), but not with gut microbiota alterations in HF. Low bacterial richness and low abundance of several genera in the Firmicutes phylum were associated with low fibre intake. Conclusions The gut microbiota in HF was characterized by decreased F/B ratio and reduced bacterial diversity associated with clinical outcome. The gut microbiota alterations in HF were partly related to low fibre intake, emphasizing the importance of diet as a covariate in future studies. Our data could provide a rationale for targeting the gut microbiota in HF with high‐fibre diet.

Purpose: Until recently, it has been believed that donating a kidney not represents any risk for development of cardiovascular disease. However, a recent Norwegian epidemiological study suggests that kidney donors have an increased long-term risk of cardiovascular mortality. The pathophysiological mechanisms linking reduced kidney function to cardiovascular disease are not known. Living kidney donors are screened for cardiovascular morbidity before unilateral nephrectomy, and are left with mildly reduced glomerular filtration rate (GFR) after donation. Therefore, they represent an unique model for investigating the pathogenesis linking reduced GFR to cardiovascular disease and cardiovascular remodelling. We present the study design of Cardiovascular rEmodelling in living kidNey donorS with reduced glomerular filtration rate (CENS), which is an investigator-initiated prospective observational study on living kidney donors. The hypothesis is that living kidney donors develop cardiovascular remodelling due to a reduction of GFR. Materials and methods: 60 living kidney donors and 60 age and sex matched healthy controls will be recruited. The controls will be evaluated to fulfil the Norwegian transplantation protocol for living kidney donors. Investigations will be performed at baseline and after 1, 3, 6 and 10 years in both groups. The investigations include cardiac magnetic resonance imaging, echocardiography, bone density scan, flow mediated dilatation, laser Doppler flowmetry, nailfold capillaroscopy, office blood pressure, 24-h ambulatory blood pressure, heart rate variability and investigation of microbiota and biomarkers for inflammation, cardiovascular risk and the calcium-phosphate metabolism. Conclusions: The present study seeks to provide new insight in the pathophysiological mechanisms linking reduced kidney function to cardiovascular disease. In addition, we aim to enlighten predictors of adverse cardiovascular outcome in living kidney donors. The study is registered at Clinical-Trials.gov (identifier: NCT03729557).

Background. Inflammation is central in development of cardiovascular disease (CVD). Aberrant function of the Nod-Like Receptor Protein 3 (NLRP3) inflammasome, a central mediator in the proinflammatory response, has been associated with atherosclerosis. The influence of genetic determinants on this inflammatory pathway and its downstream effects is less known. We aimed to investigate the frequency of a single NLRP3 gene variant according to clinical outcome in CVD and its influence on NLRP3-related markers. Methods. In this observational study, we included 1001 patients with chronic coronary syndrome. Blood samples were drawn at inclusion, including whole-blood and PAXgene tubes for DNA and RNA isolation, respectively. Allelic discrimination of the NLRP3 single nucleotide polymorphism rs10754555 was performed; and gene expression of NLRP3, Toll-Like Receptor 4, Interleukin- (IL-) 1β, and IL-18 was relatively quantified, both methods by RT-PCR. Circulating IL-6, high-sensitivity (hs) C-reactive protein, IL-18, and IL-12 were measured by enzyme-like immunosorbent assays. Clinical endpoints during 2 years (n=106) were a composite of unstable angina pectoris, myocardial infarction, nonhemorrhagic stroke, and death. Results. Minor allele frequency of the NLRP3 variant was 0.36. In all, no association of the NLRP3 variant with clinical subgroups or outcome was found, neither any significant influence on the genes’ mRNA expression or circulating protein. However, in subjects56 years, no significant effect of the variant was observed. Conclusion. The age-related reduced risk of composite endpoint in rs10754555 G-allele carriers accompanied by diminished NLRP3 mRNA expression is hypothesis generating and needs to be further explored. The study is registered at http://www.clinicaltrials.gov, with identification number NCT00222261.

BackgroundNeutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD.Material and Methods102 patients with > 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis >50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes.ResultsCirculating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p

Abstract Background Investigate effects of long-term exercise on the remodeling markers MMP-9, TIMP-1, EMMPRIN and Galectin-3 in combined type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) patients. Any associations between these biomarkers and glucometabolic variables were further assessed at baseline. Methods 137 patients (age 41–81 years, 17.2% females) were included and randomized to a 12-months exercise program or to a control group. Fasting blood samples and subcutaneous adipose tissue (AT) samples were taken at inclusion and after 12-months. The intervention was a combination of aerobic and strength training for a minimum of 150 min per week. Circulating protein levels were measured by ELISA methods and RNA was extracted from AT and circulating leukocytes. Expression levels were relatively quantified by PCR. Results After 12 months of intervention, both AT-expression and circulating levels of EMMPRIN were increased in the exercise group (p

Abstract Background Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients. Methods The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70–82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2–8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used. Results Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI. Conclusions In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging. Trial registration Clinical trials no. NCT01841944, registration date April 29, 2013.

Microvesicles (MVs) are actively secreted by cells. The NLRP3-inflammasome and the interleukin 6 (IL-6)-pathways are central in cardiovascular disease. Knowledge of how the inflammasome influences the MVs is limited. In a cross-sectional study, we assessed whether MVs in plasma associate with genes encoding inflammasome signalling in coronary thrombi. Moreover, any relationships between inflammasome activation and phosphatidylserine (PS) externalization, determined through Annexin V (AV+) labelling, and myocardial injury, assessed by cardiac troponin T (cTnT), were analysed. Intracoronary thrombi and blood samples from STEMI patients (n = 33) were investigated. mRNA of NLRP3, caspase-1, interleukin-1β (IL-1β), interleukin-18 (IL-18), IL-6, soluble IL-6-receptor (sIL-6R), and glycoprotein-130 (gp130) were isolated from the thrombi and relatively quantified by RT-PCR. MVs were analysed by flow cytometry. Total AV+ MVs, mainly reflecting hypercoagulability, correlated positively to NLRP3 gene expression (r = 0.545, p = 0.009). A similar pattern was seen for platelet, endothelial and leukocyte derived MVs, separately. The majority of the MVs were AV− (96%). Total and AV− MVs correlated inversely with IL-1β (r = −0.399 and −0.438, respectively, p < 0.05, both) and gp130 (r = −0.457 and −0.502, respectively, p < 0.05, both). No correlations between MVs and cTnT were observed. Our findings indicate an association between NLRP3-inflammasome in coronary thrombi and procoagulant AV+ MVs in STEMI patients. The inverse relationships between AV− MVs and the gene expression of inflammasome activation may indicate an immuno-dampening role of this subpopulation.

Background: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF

Objective Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.Methods In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase–DNA (MPO–DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1–3).Results Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p

Abstract Background Neutrophil extracellular traps (NETs) have recently been identified as mediators in atherothrombosis. Although NETosis in general has been suggested to be glucose dependent, the transferability to patients with acute ST-elevation myocardial infarction (STEMI) is unclear. We assessed whether the NETs markers double-stranded deoxyribonucleid acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) associated with plasma glucose and the glucometabolic status in the acute phase and 3 months after a STEMI. We also explored whether an acute glucose load resulted in upregulated NETosis by assessment of peptidylarginine deiminase 4 (PAD4) gene expression. Methods In total, 224 STEMI patients were prospectively enrolled and underwent blood sampling acutely (median 16.5 h after PCI) and after 3 months. Glucometabolic status was defined based on the results of an oral glucose tolerance test (OGTT) as normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or type 2 diabetes (T2DM). dsDNA and MPO-DNA were measured in serum, while PAD4 mRNA was measured in circulating leukocytes by RT-PCR. Results dsDNA levels were significantly correlated to plasma glucose both acutely and after 3 months (r = 0.12 and r = 0.17, both p

Abstract Background Platelet inhibition is important for patients with coronary artery disease. When dual antiplatelet therapy (DAPT) is required, a P2Y12-antagonist is usually recommended in addition to standard aspirin therapy. The most used P2Y12-antagonists are clopidogrel, prasugrel and ticagrelor. Despite DAPT, some patients experience adverse cardiovascular events, and insufficient platelet inhibition has been suggested as a possible cause. In the present review we have performed a literature search on prevalence, mechanisms and clinical implications of resistance to P2Y12 inhibitors. Methods The PubMed database was searched for relevant papers and 11 meta-analyses were included. P2Y12 resistance is measured by stimulating platelets with ADP ex vivo and the most used assays are vasodilator stimulated phosphoprotein (VASP), Multiplate, VerifyNow (VN) and light transmission aggregometry (LTA). Discussion/conclusion The frequency of high platelet reactivity (HPR) during clopidogrel therapy is predicted to be 30%. Genetic polymorphisms and drug-drug interactions are discussed to explain a significant part of this inter-individual variation. HPR during prasugrel and ticagrelor treatment is estimated to be 3–15% and 0–3%, respectively. This lower frequency is explained by less complicated and more efficient generation of the active metabolite compared to clopidogrel. Meta-analyses do show a positive effect of adjusting standard clopidogrel treatment based on platelet function testing. Despite this, personalized therapy is not recommended because no large-scale RCT have shown any clinical benefit. For patients on prasugrel and ticagrelor, platelet function testing is not recommended due to low occurrence of HPR.

Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten–eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs’ role in CVD, and underline TET2s’ role in the epigenetic regulation of lifestyle-related diseases.

Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.

Background. The Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome and the Interleukin-6 (IL-6) pathways are central mechanisms of the inflammatory response in myocardial reperfusion injury. Expanding our knowledge about the inflammasome signaling axis is important to improve treatment options. In a cross-sectional study, we aimed to study presence, localization, and genetic expression of inflammasome- and IL-6- signaling-related proteins in coronary thrombi and circulating leukocytes from ST-elevation myocardial infarction (STEMI) patients, with relation to myocardial injury and time from symptoms to PCI. Methods. Intracoronary thrombi were aspirated from 33 STEMI patients. Blood samples were drawn. mRNA of Toll-Like-Receptor-4 (TLR4), NLRP3, caspase 1, Interleukin-1β (IL1-β), Interleukin-18 (IL-18), IL-6, IL-6-receptor (IL-6R), and glycoprotein 130 (gp130) were isolated from thrombi and circulating leukocytes and relatively quantified by RT-PCR. A part of each thrombus was embedded in paraffin for histology and immunohistochemistry analyses. Results. Genes encoding the 8 markers were present in 76-100% of thrombi. Expression of TLR4 in thrombi significantly correlated to troponin T (r=0.455, p=0.013), as did NLRP3 (r=0.468, p=0.024). Troponin T correlated with expression in circulating leukocytes of TLR4 (r=0.438, p=0.011), NLRP3 (r=0.420, p=0.0149), and IL-1β (r=0.394, p=0.023). IL-6R expression in thrombi correlated significantly to troponin T (r=0.434, p=0.019), whereas gp130 was inversely correlated (r=−0.398, p=0.050). IL-6 in circulating leukocytes correlated inversely to troponin T (r=−0.421, p=0.015). There were no significant correlations between genes expressed in thrombi and time from symptom to PCI. Conclusions. The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI, in association with myocardial damage measured by troponin T. This supports the strategy of medically targeting this pathway in treating myocardial infarction and contributes to sort out optimal timing and targets for anti-inflammatory treatment. The study is registered at clinicaltrials.gov with identification number NCT02746822.

In general, aerobic exercise has a positive impact on the vascular system, but the syndrome of relative energy-deficiency in sports (RED-S) makes this impact less clear for the athlete. The present cross-sectional controlled study aimed to investigate the vascular function in female elite long-distance runners, compared to inactive women. Sixteen female elite long-distance runners and seventeen healthy controls were recruited. Assessments of vascular function and morphology included endothelial function, evaluated by flow-mediated dilatation (FMD), vascular stiffness, evaluated with pulse wave velocity (PWV), carotid artery reactivity (CAR %), and carotid intima-media thickness (cIMT). Blood samples included hormone analyses, metabolic parameters, lipids, and biomarkers reflecting endothelial activation. RED-S risk was assessed through the low energy availability in female questionnaire (LEAF-Q), and body composition was measured by dual-energy X-ray absorptiometry (DXA). We found no significant differences in brachial FMD, PWV, CAR %, cIMT, or biomarkers reflecting endothelial activation between the two groups. Forty-four percent of the runners had a LEAF-Q score consistent with being at risk of RED-S. Runners showed significantly higher HDL-cholesterol and insulin sensitivity compared to controls. In conclusion, Norwegian female elite runners had an as good vascular function and morphology as inactive women of the same age.

OBJECTIVES:Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes. METHODS:In this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA. RESULTS:In the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27-0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16-3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23-0.28, p

ObjectiveThe role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the role of NETs components in relation to myocardial function and interleukin 8 in STEMI patients with symptomatic acute heart failure.MethodsIn 61 STEMI patients developing acute heart failure within 48 hours of successful revascularization, wall motion score index (WMSI), global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography at baseline and on day 5. Blood drawn at baseline and days 1, 2 and 5 was used to quantify double-stranded DNA (dsDNA), myeloperoxidase-DNA complexes (MPO-DNA) and citrullinated histone 3 (CitH3). The area under the curve (AUC) of each NETs marker and interleukin 8 was approximated for the first 5 days.ResultsdsDNAAUC and MPO-DNAAUC correlated significantly with change in WMSI from baseline to day 5 (rs = 0.28 for both, p≤0.05), whereas NETs AUCs did not correlate with changes in GLS and LVEF. dsDNAAUC was significantly correlated with interleukin 8AUC (r = 0.40, p = 0.003). However, mixed model regression could not identify a significant effect of the NETs components on myocardial function parameters.ConclusionsIn this cohort with acute heart failure complicating STEMI, NETs components were partly correlated with myocardial function and interleukin 8 levels, yet no causal relationship between NETs components and myocardial recovery could be established.Clinical trial registrationClinicalTrials.gov, identifier: NCT00324766.

ObjectivesWe aimed to assess prevalence of left ventricular (LV) systolic and diastolic function in stable cohort of COPD patients, where LV disease had been thoroughly excluded in advance.Methods100 COPD outpatients in GOLD II-IV and 34 controls were included. Patients were divided by invasive mean pulmonary artery pressure (mPAP) in COPD-PH (≥25 mmHg) and COPD-non-PH (ResultsLV MPI ≥0.51 was found in 64.9% and 88.5% and LV strain ≤-15.8% in 62.2.% and 76.9% in the COPD-non-PH and COPD-PH patients, respectively. Similarly, LV MPI and LV strain were impaired even in patients with mPAP ConclusionsSubclinical LV systolic dysfunction was a frequent finding in this cohort of COPD patients, even in those with normal pulmonary artery pressure. Evidence of LV diastolic dysfunction was hardly present as measured by conventional echo indices.

Background. Type 1 diabetes is a chronic disease including hyperglycemia and accelerated atherosclerosis, with high risk of micro- and macrovascular complications. Circulating microvesicles (cMVs) are procoagulant cell fragments shed during activation/apoptosis and discussed to be markers of vascular dysfunction and hypercoagulability. Limited knowledge exists on hypercoagulability in young diabetics. We aimed to investigate cMVs over a five-year period in children/adolescents with type 1 diabetes compared with controls and any associations with glycemic control and cardiovascular risk factors. We hypothesized increased shedding of cMVs in type 1 diabetes in response to vascular activation. Methods. The cohort included type 1 diabetics (n=40) and healthy controls (n=40), mean age 14 years (range 11) at inclusion, randomly selected from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Citrated plasma was prepared and stored at -80°C until cMV analysis by flow cytometry. Results. Comparable levels of Annexin V (AV+) cMVs were observed at inclusion. At five-year follow-up, total AV+ cMVs were significantly lower in subjects with type 1 diabetes compared with controls; however, no significant differences were observed after adjusting for covariates. In the type 1 diabetes group, the total AV+, tissue factor-expressing AV+/CD142+, neutrophil-derived AV+/CD15+ and AV+/CD45+/CD15+, and endothelial-derived AV+/CD309+ and CD309+/CD34+ cMVs were inversely correlated with HbA1c (r=‐0.437, r=‐0.515, r=‐0.575, r=‐0.529, r=‐0.416, and r=‐0.445, respectively; all p≤0.01), however, only at inclusion. No significant correlations with cardiovascular risk factors were observed. Conclusions. Children/adolescents with type 1 diabetes show similar levels of AV+ cMVs as healthy controls and limited associations with glucose control. This indicates that our young diabetics on intensive insulin treatment have preserved vascular homeostasis and absence of procoagulant cMVs.

Complement activation and neutrophil extracellular traps (NETs) have both been suggested to drive atherosclerotic plaque progression. Although experimental studies suggest interplay between these two innate immunity components, the relevance in patients with coronary artery disease (CAD) is unclear. The aim of this study was to assess associations between complement activation and NETs in patients with stable CAD and examine the role of complement activation on clinical outcome. Blood samples from a cohort of patients with angiographically verified stable CAD (n=1001) were analyzed by ELISA for the terminal complement complex (TCC) and by relative quantification for gene expression of the C5a receptor 1 (C5aR1) as markers of complement activation. As markers of NETs, dsDNA was analyzed by fluorescent nucleic acid stain and myeloperoxidase-DNA (MPO-DNA) by ELISA. Clinical outcome was defined as unstable angina, nonhemorrhagic stroke, acute myocardial infarction (MI), or death (n=106, whereof 36 MI). Levels of TCC and C5aR1 were not significantly correlated to dsDNA (TCC: r=−0.045, p=0.153; C5aR1: r=−0.060, p=0.434) or MPO-DNA (TCC: r=0.026, p=0.414; C5aR1: r=0.123, p=0.107). When dividing TCC and C5aR1 levels into quartiles (Q), levels of MPO-DNA differed significantly across quartiles (TCC: p=0.008, C5aR1: 0.049), while dsDNA did not (TCC: p=0.181, C5aR1: p=0.771). Patients with TCC levels in Q4 had significantly higher levels of MPO-DNA than Q1-3 (p=0.019), and C5aR1 levels in Q3-4 had significantly higher levels of MPO-DNA than Q1-2 (p=0.046). TCC levels did not differ between patients experiencing a clinical endpoint or not, but high levels were associated with increased risk of acute MI (OR. 1.97, 95% CI: 0.99-3.90, p=0.053) during two-year follow up, also when adjusted for relevant covariates. In conclusion, TCC and C5aR1 were moderately associated with the NET marker MPO-DNA, and TCC levels were related to the risk of future MI in this cohort of patients with stable CAD.

Abstract Background Metabolic syndrome (MetS) is a cluster of conditions that conjoined represents a 1.5–2.5 fold increased risk of developing cardiovascular disease (CVD). Recent studies have reported that gut dysbiosis and leakage of bacterial components, may contribute to the metabolic disturbances and systemic inflammation observed in subjects with MetS. Chronic exposure to lipopolysaccharide (LPS) has been shown to induce features of MetS in experimental studies. LPS interacts with the innate immune system, facilitated through LPS-binding protein (LBP) and the co-receptor CD14, both regarded as markers of gut leakage. Purpose We investigated whether circulating levels of LBP and sCD14 are associated with the presence of MetS and its components, and further any association with systemic inflammation. Methods We examined 482 men, aged between 65 and 75 years, all at high CVD risk. MetS criteria’s according to the US National Cholesterol Education Program Adult Treatment Panel III were met in 182 subjects (38%). Results Levels of LBP and sCD14 did not differ between individuals with and without MetS. However, a trend towards increased risk of MetS through quartiles of LBP was observed (p = 0.05). Individuals in the highest quartile (Q4), had an increased risk of MetS (OR = 1.76, 95% CI (1.04–3.00), compared to the lowest quartile (Q1) (p = 0.04). With regard to the separate constituents of MetS, patients who met the waist circumference criterion had significant higher concentration of LBP compared to those who did not (p = 0.04). We also found a weak, but significant correlation between LBP and waist circumference (r = 0.10, p = 0.03). Moderate, yet significant correlations were observed between both LBP and sCD14 and several markers of systemic inflammation (r = 0.1–0.23; p

Abstract HIV infection and type 2 diabetes are associated with altered gut microbiota, chronic inflammation, and increased cardiovascular risk. We aimed to investigate the combined effect of these diseases on gut microbiota composition and related metabolites, and a potential relation to endothelial dysfunction in individuals with HIV-infection only (n = 23), diabetes only (n = 16) or both conditions (n = 21), as well as controls (n = 24). Fecal microbiota was analyzed by Illumina sequencing of the 16 S rRNA gene. Markers of endothelial dysfunction (asymmetric dimethylarginine [ADMA]), tryptophan catabolism (kynurenine/tryptophan [KT]-ratio), and inflammation (neopterin) were measured by liquid chromatography-tandem mass spectrometry. The combination of HIV and type 2 diabetes was associated with reduced gut microbiota diversity, increased plasma KT-ratio and neopterin. Microbial genes related to tryptophan metabolism correlated with KT-ratio and low alpha diversity, in particular in HIV-infected with T2D. In multivariate analyses, KT-ratio associated with ADMA (β = 4.58 [95% CI 2.53–6.63], p

Abstract Background Atrial fibrillation (AF) confers a hypercoagulable state; however, it is not clear whether restoration of sinus rhythm is associated with normalisation of markers of thrombogenesis. We studied the impact of sustained sinus rhythm on prothrombotic markers, and their predictive abilities in foreseeing rhythm outcome after cardioversion. Methods In a double blind, placebo-controlled study, 171 patients referred for electrical cardioversion of persistent AF were randomised to receive candesartan or placebo for 3-6 weeks before and 6 months after cardioversion. Endogenous thrombin potential (ETP), prothrombin fragment 1 + 2 (F1 + 2) and D-dimer were measured before cardioversion and at end of study. These markers were also measured in a reference group comprising 49 subjects without AF. Results The markers remained unchanged in those 28 patients who maintained sinus rhythm. Discontinuation of warfarin treatment in a subset of 13 low-risk patients in sinus rhythm was associated with significantly higher levels of D-dimer and F1 + 2 compared to the reference group; D-dimer (456 ng/mL (276, 763) vs. 279 ng/mL (192, 348), p = 0.002) and F1 + 2 (700 pmol/L (345, 845) vs. 232 pmol/L (190, 281), p

Dihomo-gamma-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid (PUFA) derived from linoleic acid (LA). The LA:DGLA ratio reflects conversion from LA to DGLA. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. Aims: To assess the association of DGLA and LA:DGLA with total death as a primary aim and incident cardiovascular events as a secondary objective. Methods: Baseline samples from 1002 patients, aged 70 to 82 years, included 2–8 weeks after an MI and followed for 2 years, were used. Major adverse clinical events (MACE) consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. Cox regression analysis was used to relate serum n-6 PUFA phospholipid levels (%wt) to the risk of MACE, adjusting for the following: (1) age, sex and body mass index (BMI); (2) adding baseline cod liver oil supplementation; (3) adding prevalent hypertension, chronic kidney disease and diabetes mellitus. Results: Median DGLA level in serum phospholipids was 2.89 (Q1–Q3 2.43–3.38) %wt. DGLA was inversely related to LA and LA:DGLA ratio. There were 208 incident cases of MACE and 55 deaths. In the multivariable analysis, the hazard ratio (HR) for the total death in the three higher quartiles (Q2–4) of DGLA as compared to Q1 was 0.54 (0.31–0.95), with p = 0.03 (Model-1), 0.50 (0.28–0.91), with p = 0.02 (Model-2), and 0.47 (0.26–0.84), with p = 0.012 (Model-3), and non-significant for MACE. Risk of MACE (Model 3) approached borderline significance for LA:DGLA in Q2–4 vs. Q1 [HR 1.42 (1.00–2.04), p = 0.052]. Conclusions: Low levels of DGLA were related to a high LA:DGLA ratio and risk of total death in elderly patients with recent MI.

Elevated levels of gut leakage markers have been shown after strenuous exercise in healthy individuals. Any association between a temporary increase in these markers and the presence of coronary artery disease (CAD) is unknown. We therefore aimed to explore circulating gut leakage markers in response to a bout of strenuous exercise in patients with symptoms of CAD. Patients referred to exercise stress testing due to symptoms of CAD were included (n = 287). A maximal exercise ECG stress test was performed and venous blood samples were drawn at rest and within five minutes after, for analysis of soluble cluster of differentiation 14 (sCD14), lipopolysaccharide-binding protein (LBP), intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide (LPS) and gene expression of toll-like receptor 4 (TLR4) in circulating leukocytes. Patients then underwent coronary angiography. LPS, LBP and sCD14 increased significantly after strenuous exercise in patients with symptoms of CAD, suggesting that even short bouts of vigorous exercise are associated with gut leakage. The gene expression of TLR4 decreased significantly after exercise, possibly as a negative feedback to the increase in LPS. There were no differences in exercise-induced changes between the groups of CAD, suggesting gut leakage to be independent of the presence of CAD.

Endothelial vasodilatory function is dependent on the NO synthesis from L-arginine by endothelial NO-synthetase (eNOS). eNOS can be inhibited by asymmetric dimethylarginine (ADMA) by competitive inhibition on the binding site, and symmetric dimethylarginine (SDMA) can reduce the L-arginine availability intracellularly through competing for transport over the cellular membrane. To study the NO synthesis after prolonged exercise, we assessed circulatory L-arginine, the L-arginine/ADMA ratio, and SDMA before, after, and on the day after the Norseman Xtreme triathlon, an Ironman distance triathlon. We found significantly reduced levels of L-arginine and the L-arginine/ADMA ratio and increased levels of SDMA after the race (all p < 0.05). L-arginine rose toward baseline levels the day after the race, but ADMA increased beyond baseline levels, and SDMA remained above baseline the day after the race. The reduced levels of L-arginine and the L-arginine/ADMA ratio, and increased SDMA, after the race indicate a state of reduced capability of NO production. Increased levels of ADMA and SDMA, and reduced L-arginine/ADMA ratio, as seen the day after the race, are known risk markers of atherosclerosis and warrant further studies.

We assessed endothelial function by flow-mediated dilatation (FMD), levels of the NO-precursor L-arginine, and markers of endothelial inflammation before, at the finish line, and one week after the Norseman Xtreme triathlon. The race is an Ironman distance triathlon with a total elevation of 5200 m. Nine male participants were included. They completed the race in 14.5 (13.4–15.3) h. FMD was significantly reduced to 3.1 (2.1–5.0)% dilatation compared to 8.7 (8.2–9.3)% dilatation before the race (p < 0.05) and was normalized one week after the race. L-arginine showed significantly reduced levels at the finish line (p < 0.05) but was normalized one week after the race. Markers of endothelial inflammation E-Selectin, VCAM-1, and ICAM-1 all showed a pattern with increased values at the finish line compared to before the race (all p < 0.05), with normalization one week after the race. In conclusion, we found acutely reduced FMD with reduced L-arginine levels and increased E-Selectin, VCAM-1, and ICAM-1 immediately after the Norseman Xtreme triathlon. Our findings indicate a transient reduced endothelial function, measured by the FMD-response, after prolonged strenuous exercise that could be explained by reduced NO-precursor L-arginine levels and increased endothelial inflammation.

Abstract Background The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments. Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years. Methods Stable aspirin-treated CAD patients (n = 999) from the ASCET trial. RPR was assessed by PFA-100. ADAMTS13 antigen and activity were analysed using chromogenic assays. Endpoints were a composite of acute myocardial infarction, stroke and death. Results The number of patients with high RPR was 258 (25.8%). Their serum thromboxane B2 (TxB2) levels were low, indicating inhibition of COX-1. They had significantly lower levels of ADAMTS13 antigen compared to patients with low RPR (517 vs 544 ng/mL, p = 0.001) and significantly lower ADAMTS13 activity (0.99 vs 1.04 IU/mL, p = 0.020). The differences were more pronounced when relating RPR to ratios of vWF/ADAMTS13 antigen and vWF/ADAMTS13 activity (p