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Highlighted articles November

Volume 266 Issue November 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Associations between biomarkers or risk factors and the presence or incidence of diseases may reflect causality, reverse causality or even innocent bystanders. Likewise, off-target effects of interventions are not only the cause of adverse events but can lead to wanted positive outcomes. This issue of Atherosclerosis contains several examples of experiments and studies addressing this problem of bystanders and off-target effects.

Issue highlights


    Highlighted articles

    Prognostic value of lipoprotein-associated phospholipase A2 mass for all-cause mortality and vascular events within one year after acute ischemic stroke

    Experimental studies demonstrate that lipoprotein-associated phospholipase A2 (Lp-PLA2) exerts its effect on cardiovascular disease (CVD) through involvement in the evolution of atherosclerosis. Accumulating epidemiological studies have reported strong associations of Lp-PLA2 with CVD and stroke in the general population, as well as in the populations of metabolic syndrome, diabetes, and coronary heart disease (CHD). It remains unclear whether higher levels of Lp-PLA2 mass predict longer-term risks of all-cause mortality and vascular events in patients with acute ischemic stroke. Han et al. assessed the prognostic value of the Lp-PLA2 mass after acute ischemic stroke.

    They examined Lp-PLA2 mass among 3401 participants enrolled in the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was all-cause mortality. Hazards regression models were used to estimate the risk of outcomes and to assess the independent associations between baseline Lp-PLA2 mass and outcomes after adjustment for variables in models 1, 2, and 3 [further adjusted for low-density lipoprotein cholesterol (LDL-C)].

    Overall, 3278 patients completed the follow-up, during which, 188 all-cause death events occurred. The Kaplan-Meier survival curve showed that the cumulative incidence rate of all-cause mortality increased across quartiles of Lp-PLA2 mass. Compared with the lowest quartile of Lp-PLA2, the HRs for the highest quartile of Lp-PLA2 were 1.89, 2.16, and 2.17 for all-cause mortality after adjusting for the covariables in models 1, 2, and 3, respectively. In addition, patients in the highest quartile of Lp-PLA2 mass coupled with higher LDL-C had a significantly highest risk of all-cause mortality.

    The elevated Lp-PLA2 mass was associated with all cause-death independently of other risk factors within one year after acute ischemic stroke.

    High-sensitivity C-reactive protein levels and health status outcomes after myocardial infarction

    While high-sensitivity C-reactive protein (hs-CRP) is a marker of inflammation and higher cardiovascular risk, its association with health status (symptoms, function and quality of life) after acute myocardial infarction (AMI) is unknown.

    Pokharel et al. compared 1-year generic (Medical Outcome Study Short Form-12 and Euro Quality of Life Visual Analog Scale) and disease-specific (Seattle Angina Questionnaire) health status outcomes among 3410 patients with AMI from the TRIUMPH and VIRGO studies, with hs-CRP ≥2 mg/L vs. <2 mg/L. In hierarchical linear regression models, the authors examined the association of 30-day hs-CRP levels with 1-year health status without adjustment, after adjusting for 30-day health status, and after adjusting for demographic, socioeconomic, disease severity/comorbidities and treatment characteristics.

    The median 30-day hs-CRP was 2.6 mg/L and 59% had hs-CRP ≥2 mg/L. Statin therapy was used in 92% of patients at hospital discharge. Thirty-day hs-CRP ≥2 mg/L was inversely associated with all 1-year health status measures in unadjusted and partially adjusted models, but not in fully-adjusted models. Results were similar when hs-CRP was analyzed as a continuous variable.

    While elevated hs-CRP 30 days after AMI was associated with worse health status in unadjusted analyses, this was not significant after adjusting for comorbidities, suggesting that hs-CRP may be a marker of comorbidities associated with worse health status. Whether reducing inflammation in AMI patients will improve health status should be tested in ongoing trials.

    Soluble HLA-DR serum levels are associated with smoking but not with acute coronary syndrome

    Elevated soluble HLA-DR (sHLA-DR) serum levels have been reported in HLA class II-associated inflammatory disorders. Tolva et al. previously showed that the HLA class II allele HLA-DRB1*01 may predispose to acute coronary syndromes (ACS). However, sHLA-DR serum levels have never been studied in ACS.

    sHLA-DR serum levels in serum were measured in 477 ACS patients and 475 area- and sex-matched controls by sandwich enzyme-linked immunosorbent assay. Binary logistic regression and ordinal logistic regression analyses adjusted for clinical parameters were conducted to evaluate the associations of sHLA-DR levels.

    ACS patients had lower sHLA-DR serum levels compared to controls. After adjustment for smoking status, this association was no longer significant. This was explained by the notion that current smoking was inversely associated with sHLA-DR levels in both cases and controls. A similar effect was not observed with other cardiovascular risk factors.

    The results indicate that lower sHLA-DR levels are associated with smoking, but not with ACS. This is an important finding because previous studies of sHLA-DR have not accounted for the possible associations between smoking and sHLA-DR levels. Further studies are required to confirm these novel results and explore the mechanisms behind the observed associations.

    Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

    Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, Strawbridge et al. took advantage of a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

    They studied the high CVD-risk IMPROVE cohort, which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes were excluded from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

    A proinsulin locus on chromosome 15 (rs8029765) was identified and replicated in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline (IMT)mean and IMTmax (the primary cIMT phenotypes), but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

    While proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

    Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions

    In the ATHENA trial, dronedarone, a multichannel-blocking antiarrhythmic drug pharmacologically related to amiodarone, but with structural modifications that reduce the risk of associated adverse effects, decreased the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF). This result cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. In this study, Urooj Zafar et al. aimed to investigate any direct effect of dronedarone on hemostatic parameters (i.e. blood thrombogenicity), independent of its antiarrhythmic effects.

    Blood samples from patients with cardiovascular disease, taking no anticoagulant or antiplatelet medication except aspirin, were incubated with dronedarone's active metabolite SR35021A. The concentrations of the active metabolite were calculated to achieve final levels of 66 ng/ml (am-L) and 119 ng/ml (am-H), corresponding to the minimum and maximum mean Cmax achieved after repeated oral doses of dronedarone, 400 mg BID. A third aliquot of blood was used as control. Antithrombotic effects of dronedarone were assessed using coagulation time (CT), clot formation rate (CFR) and maximum clot firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide-6 (TRAP).

    The authors showed that compared to the control, am-L and am-H prolonged mean CT. Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). am-H also reduced ADP- and TRAP-induced platelet aggregation.

    Dronedarone directly inhibits platelet function and coagulation parameters on human blood in vitro independently of its antiarrhythmic actions. This helps partly explain its effect on stroke reduction in the ATHENA trial, suggesting that reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve the understanding of the mechanisms involved.


    Diclofenac but not celecoxib improves endothelial function in rheumatoid arthritis: A study in adjuvant-induced arthritis

    Rheumatoid arthritis (RA) is associated with increased risk of cardiovascular (CV) events and mortality. The CV risk in RA patients is roughly 2-fold that of the general population. Non-steroidal anti-inflammatory drugs (NSAIDs), including traditional NSAIDs (tNSAIDs, unspecific cyclooxygenase (COX) inhibitors) and coxibs (selective COX-2 inhibitors), are often prescribed in combination with antirheumatic drugs to manage painful symptoms in RA. In the general population, results from clinical trials, epidemiological studies, and meta-analysis revealed that coxibs, as well as some tNSAIDs, are associated with an increased relative risk of CV events. In the RA population, the few available data on the effects of NSAIDs on CV risk are not totally congruent. Verhoeven et al. aimed at investigating the effect of celecoxib (COX-2 selective inhibitor) and diclofenac (non-selective COX inhibitor) on endothelial function, and at identifying the underlying mechanisms in adjuvant-induced arthritis (AIA).

    At the first signs of AIA, diclofenac, celecoxib or saline was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of NOS (nitric oxide synthase), arginase, endothelium-derived hyperpolarizing factor (EDHF) and superoxide anions (O2−°) production. Aortic expression of eNOS, Ser1177-phospho-eNOS, COX-2, arginase-2, p22phox and p47phox was evaluated. Arthritis scores, blood pressure, glycaemia and serum asymmetric dimethylarginine (ADMA) levels were measured.

    Diclofenac and celecoxib significantly reduced arthritis score to the same extent. As compared to vehicle-treated AIA, celecoxib did not change whereas diclofenac improved endothelial function through increased EDHF production, decreased arginase activity and expression, decreased superoxide anions production and expression of p22phox and p47phox. Diclofenac but not celecoxib significantly enhanced blood pressure and serum ADMA levels. Glycaemia was unchanged by both treatments.

    This study reveals that the effect of NSAIDs on endothelial function cannot be extrapolated from their impact on arthritis severity and suggest that changes in blood pressure and plasma ADMA levels may not be useful to predict CV risk of NSAIDs in RA.

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