Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

Background - Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death. Methods - Outcome was assessed at six months and defined by cerebral performance category scale (1−2; good outcome, 3−5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule. Results - Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p Conclusion - Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients

Sea ice reduction drives genetic differentiation among Barents Sea polar bears

Loss of Arctic sea ice owing to climate change is predicted to reduce both genetic diversity and gene flow in ice-dependent species, with potentially negative consequences for their long-term viability. Here, we tested for the population-genetic impacts of reduced sea ice cover on the polar bear (Ursus maritimus) sampled across two decades (1995–2016) from the Svalbard Archipelago, Norway, an area that is affected by rapid sea ice loss in the Arctic Barents Sea. We analysed genetic variation at 22 microsatellite loci for 626 polar bears from four sampling areas within the archipelago. Our results revealed a 3–10% loss of genetic diversity across the study period, accompanied by a near 200% increase in genetic differentiation across regions. These effects may best be explained by a decrease in gene flow caused by habitat fragmentation owing to the loss of sea ice coverage, resulting in increased inbreeding of local polar bears within the focal sampling areas in the Svalbard Archipelago. This study illustrates the importance of genetic monitoring for developing adaptive management strategies for polar bears and other ice-dependent species

The Andersen aerobic fitness test: New peak oxygen consumption prediction equations in 10 and 16-year olds

This is the peer reviewed version of the following article: Aadland, E., Andersen, L. B., Lerum, Ø., & Resaland, G. K. (2018). The Andersen aerobic fitness test: New peak oxygen consumption prediction equations in 10 and 16-year olds. Scandinavian Journal of Medicine & Science in Sports, 28, 862-872, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/sms.12985. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Measurement of aerobic fitness by determining peak oxygen consumption (VO2peak) is often not feasible in children and adolescents, thus field tests such as the Andersen test are required in many settings, for example in most school‐based studies. This study provides cross‐validated prediction equations for VO2peak based on the Andersen test in 10 and 16‐year‐old children. We included 235 children (n = 113 10‐year olds and 122 16‐year olds) who performed the Andersen test and a progressive treadmill test to exhaustion to determine VO2peak. Joint and sex‐specific prediction equations were derived and tested in 20 random samples. Performance in terms of systematic (bias) and random error (limits of agreement) was evaluated by means of Bland‐Altman plots. Bias varied from −4.28 to 5.25 mL/kg/min across testing datasets, sex, and the 2 age groups. Sex‐specific equations (mean bias −0.42 to 0.16 mL/kg/min) performed somewhat better than joint equations (−1.07 to 0.84 mL/kg/min). Limits of agreement were substantial across all datasets, sex, and both age groups, but were slightly lower in 16‐year olds (5.84‐13.29 mL/kg/min) compared to 10‐year olds (9.60‐15.15 mL/kg/min). We suggest the presented equations can be used to predict VO2peak from the Andersen test performance in children and adolescents on a group level. Although the Andersen test appears to be a good measure of aerobic fitness, researchers should interpret cross‐sectional individual‐level predictions of VO2peak with caution due to large random measurement errors.acceptedVersio

The gut microbiome in coronary artery disease and heart failure: Current knowledge and future directions

Host-microbiota interactions involving inflammatory and metabolic pathways have been linked to the pathogenesis of multiple immune-mediated diseases and metabolic conditions like diabetes and obesity. Accumulating evidence suggests that alterations in the gut microbiome could play a role in cardiovascular disease. This review focuses on recent advances in our understanding of the interplay between diet, gut microbiota and cardiovascular disease, with emphasis on heart failure and coronary artery disease. Whereas much of the literature has focused on the circulating levels of the diet- and microbiota-dependent metabolite trimethylamine-N-oxide (TMAO), several recent sequencing-based studies have demonstrated compositional and functional alterations in the gut microbiomes in both diseases. Some microbiota characteristics are consistent across several study cohorts, such as a decreased abundance of microbes with capacity for producing butyrate. However, the published gut microbiota studies generally lack essential covariates like diet and clinical data, are too small to capture the substantial variation in the gut microbiome, and lack parallel plasma samples, limiting the ability to translate the functional capacity of the gut microbiomes to actual function reflected by circulating microbiota-related metabolites. This review attempts to give directions for future studies in order to demonstrate clinical utility of the gut-heart axis

Long-term survival in patients with acute myocardial infarction and out-of-hospital cardiac arrest: A prospective cohort study

Aim: To compare short- and long-term survival in patients admitted to hospital after acute myocardial infarction (AMI) with and without out-of-hospital cardiac arrest (OHCA). Methods: Prospective cohort study of all AMI patients admitted to Oslo University Hospital Ulleval from September 1, 2005 to December 31, 2011. All-cause mortality was obtained from the Norwegian Cause of Death Registry with censoring date December 31, 2013. Cumulative survival was assessed with the Kaplan-Meier and the Life-table method. Logistic- and Cox regression were used for risk comparisons. Results: We identified 404 AMI patients with OHCA and 9425 AMI patients without. AMI patients without OHCA were categorized as ST-elevation myocardial infarction (STEMI, n = 4522) or non-STEMI (NSTEMI, n = 4903). Mean age was 63.6 ± standard deviation (SD) 12.5, 63.8 ± 13.1 and 69.7 ± 13.6 years in OHCA, STEMI and NSTEMI, respectively. Coronary angiography with subsequent percutaneous coronary intervention if indicated, was performed in 87% of OHCA, 97% of STEMI and 80% of NSTEMI patients. Thirty-day survival was 63%, 94% and 94%, and 8-year survival was 49%, 74%, and 57%, respectively. Among patients surviving the first 30 days, no significant difference in risk during long-term follow-up was found (adjusted Hazard Ratio (aHR)OHCAvsSTEMI 1.15 [95% CI 0.82–1.60], aHROHCAvsNSTEMI 0.89 [95% CI 0.64-1.24]). Conclusions: Long-term survival after OHCA due to AMI was good, with 49% of admitted patients being alive after eight years. Although short-term mortality remained high, OHCA patients alive after 30 days had similar long-term risk as AMI patients without OHCA

The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium

Aims We recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors. Methods Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors. Results OR-1896 evoked a maximum PIR of 33±10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89±14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5±5.3%) or milrinone (3.2±4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response. Conclusion The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI

Objective Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI. Methods We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively. Results IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality. Conclusion Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention

Myocardial salvage is reduced in primary PCI-treated STEMI patients with microvascular obstruction, demonstrated by early and late CMR.

OBJECTIVES: This study evaluates the association between microvascular obstruction and myocardial salvage, determined by cardiac magnetic resonance performed both in the acute stage of myocardial infarction and after 4 months. METHODS: In patients with acute ST-elevation myocardial infarction treated by primary percutaneous coronary intervention, myocardial salvage, infarct size, left ventricular volumes, and ejection fraction were assessed by early (1-4 days) and follow-up (4 months) cardiac magnetic resonance. These variables were related to the presence or absence of microvascular obstruction at early investigation. Myocardial salvage was determined by: (1) myocardium at risk and infarct size measured in the acute stage and (2) myocardium at risk, measured acutely, and infarct size measured after 4 months. Multivariate analyses were performed, adjusting for clinical confounders at baseline. RESULTS: Microvascular obstruction was present in 49 of 94 included patients, (52%). Myocardial salvage was significantly reduced in patients with microvascular obstruction, compared to those without: 23% vs. 38%, measured acutely, and 39.8% vs. 65.4%, after 4 months (p<0.001). The presence of microvascular obstruction was significantly and independently associated with large infarct size, lower left ventricular ejection fraction, and larger left ventricular end-systolic volume. CONCLUSION: The presence of microvascular obstruction demonstrated by cardiac magnetic resonance early after infarction was associated with impaired myocardial salvage. This association was more marked when based on measurement of infarct size after 4 months compared to assessment in the acute stage

Association of interleukin 8 and myocardial recovery in patients with ST-elevation myocardial infarction complicated by acute heart failure.

No data from controlled trials exists regarding the inflammatory response in patients with de novo heart failure (HF) complicating ST-elevation myocardial infarction (STEMI) and a possible role in the recovery of contractile function. We therefore explored the time course and possible associations between levels of inflammatory markers and recovery of impaired left ventricular function as well as levosimendan treatment in STEMI patients in a substudy of the LEvosimendan in Acute heart Failure following myocardial infarction (LEAF) trial.A total of 61 patients developing HF within 48 hours after a primary PCI-treated STEMI were randomised double-blind to a 25 hours infusion of levosimendan or placebo. Levels of IL-6, CRP, sIL-6R, sgp130, MCP-1, IL-8, MMP-9, sICAM-1, sVCAM-1 and TNF-α were measured at inclusion (median 22 h, interquartile range (IQR) 14, 29 after PCI), on day 1, day 2, day 5 and 6 weeks. Improvement in left ventricular function was evaluated as change in wall motion score index (WMSI) by echocardiography.Only circulating levels of IL-8 at inclusion were associated with change in WMSI from baseline to 6 weeks, r = ÷ 0.41 (p = 0.002). No association, however, was found between IL-8 and WMSI at inclusion or peak troponin T. Furthermore, there was a significant difference in change in WMSI from inclusion to 6 weeks between patients with IL-8 levels below, compared to above median value, ÷ 0.44 (IQR ÷ 0.57, ÷ 0.19) vs. ÷ 0.07 (IQR ÷ 0.27, 0.07), respectively (p < 0.0001). Levosimendan did not affect the levels of inflammary markers compared to control.High levels of IL-8 in STEMI patients complicated with HF were associated with less improvement in left ventricular function during the first 6 weeks after PCI, suggesting a possible role of IL-8 in the reperfusion-related injury of post-ischemic myocardium. Further studies are needed to confirm this hypothesis.ClinicalTrials.gov NCT00324766