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Highlighted articles May

Volume 260 Issue May 2017

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

The wish for individualized treatment, but also the avoidance of under- and overtreatment, fuels the search for novel biomarkers, which improve the prognostic value of established clinical measures and risk factors. Such novel biomarkers need validation in cohort studies. This issue of Atherosclerosis contains several articles, which report on the outcome of such validation studies, some approving some disproving the clinical utility.

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    Highlighted articles

    Immature platelet fraction and the extent of coronary artery disease: A single centre study

    Immature platelet fraction (IPF) represents the quote of younger and larger sized circulating platelets, a potential marker of platelet reactivity and major cardiovascular events. Verdoia and colleagues aimed at assessing the relationship between IPF levels and the prevalence and extent of coronary artery disease (CAD) in patients undergoing coronary angiography.

    A cohort of 1789 consecutive patients, undergoing coronary angiography in a single centre, were included in the study. Significant CAD was defined as the finding of at least one vessel with a stenosis >50%, while severe CAD was defined as left main and/or three-vessel disease. IPF levels were measured at admission by routine blood cells count and patients were divided according to quartiles values of IPF.

    The results show a direct relationship between IPF and active smoking, non-acute coronary syndrome as indication to angiography, higher levels of haemoglobin and uric acid, and lower platelet count. Angiographic features did not significantly differ according to quartiles values of IPF, but for a lower degree of TIMI (Thrombolysis In Myocardial Infarction) flow in patients with a higher percentage of reticulated platelets and a higher rate of lesions involving bifurcations. Moreover, IPF levels affect neither the prevalence of CAD nor of severe left main/three-vessel CAD.

    In conclusion, the present study shows that among patients undergoing coronary angiography, IPF is not associated with the prevalence and extent of coronary artery disease.


    Autoantibodies and immune complexes to oxidation-specific epitopes and progression of aortic stenosis: Results from the ASTRONOMER trial

    Elevated levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids associated with apolipoprotein B-100 (OxPL-apoB) predict the progression of pre-existing mild-to-moderate calcific aortic valve stenosis (CAVS). Whether indirect markers of oxidation-specific epitopes (OSE) are also predictive of such progression is unknown.

    The association between IgG and IgM autoantibodies, malondialdehyde-modified low density lipoprotein (MDA-LDL), IgG and IgM apolipoprotein B immune complexes (apoB-IC) and the hemodynamic progression rate of CAVS was determined in the ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) trial. In this study, Capoulade et al. measured the plasma levels of IgG and IgM MDA-LDL and apoB-IC from samples of 220 patients with mild-to-moderate CAVS participating in the ASTRONOMER trial. The endpoint was the progression rate of CAVS, measured by the annualized increase in peak aortic jet velocity (Vpeak) over a median follow-up of 3.5 years.

    The authors found that there was no difference in the progression rate of CAVS across tertiles of IgG and IgM MDA-LDL and apoB-IC levels. After multivariable analysis, no marker reached significance level to predict faster CAVS progression or need for aortic valve replacement (AVR). There was no interaction between the OSE antibody titers and plasma levels of Lp(a) or OxPL-apoB, as well as age, with regards to the progression rate of CAVS.

    Autoantibody titers to MDA-LDL and apoB-IC, which are an indirect measurement of OSE, unlike direct measurements of OxPL-apoB or their major lipoprotein carrier Lp(a), do not predict the progression of CAVS or need for AVR.

    Blood soluble Fas levels and mortality from cardiovascular disease in middle-aged Japanese: The JACC study

    Limited evidence exists on the relationship between apoptosis and cardiovascular disease in population-based samples. Iso et al. assessed whether blood soluble Fas (sFas) levels are associated with mortality from cardiovascular diseases.

    The authors performed a nested case-control study as part of a large prospective cohort, the Japan Collaborative Cohort (JACC) Study. sFas levels were measured in serum samples of 37,769 subjects (cases and controls), matched for sex, age, area of residence and year of serum storage. Conditional logistic regression models were used to calculate odds ratio of mortality from stroke and stroke types, according to quartiles and 1-SD increment of sFas levels.

    During the 9-year follow-up (1988–1997), 233 (121 in men and 112 in women) deaths from total stroke occurred, comprising 49 subarachnoid hemorrhages, 55 intraparenchymal hemorrhages, 71 ischemic strokes, and 97 coronary heart diseases. After adjustment for cardiovascular risk factors, the multivariable odds ratio of subarachnoid hemorrhage associated with a 1-SD increment of sFas was 4.04. No association was found between blood sFas levels and risk of intraparenchymal hemorrhage, ischemic stroke or coronary heart disease.

    The results show that higher blood sFas levels are associated with higher mortality from subarachnoid hemorrhage, suggesting a potential role of apoptosis factors in the development or prognosis of subarachnoid hemorrhage.


    Galectin-3 binding protein, coronary artery disease and cardiovascular mortality: Insights from the LURIC study

    Galectin-3 binding protein (Gal-3BP) has been associated with inflammation and cancer, however, its role in coronary artery disease (CAD) and cardiovascular outcome remains unclear.

    Gleissner et al. measured the Gal-3BP plasma levels in 2922 individuals from the LURIC Study. All-cause and cardiovascular mortality was assessed by Kaplan-Meier analysis and Cox proportional hazards regression. Causal involvement of Gal-3BP was tested for by Mendelian randomization. Gal-3BP effects on human monocyte-derived macrophages were determined in vitro.

    During 8.8 ± 3.0 years, 866 individuals died, 654 of cardiovascular causes. There was a significant increase in all-cause and cardiovascular mortality with increasing Gal-3BP quintiles. After thorough adjustment, all-cause mortality remained significantly increased in the fifth Gal-3BP quintile, and cardiovascular mortality remained increased in Gal-3BP quintiles two to five. Gal-3BP levels were not associated with diagnosis and extent of coronary artery disease. In addition, Mendelian randomization did not show a direct causal relationship between Gal-3BP levels and mortality. Gal-3BP levels were, however, independently associated with markers of metabolic and inflammatory distress. In vitro, Gal-3BP induced a pro-inflammatory response in human monocyte-derived macrophages. Adding Gal-3BP levels to the ESC SCORE improved risk assessment in patients with ESC SCORE-based risk >5%.

    The results show that in a large clinical cohort of CAD patients, Gal-3BP levels are independently associated with all-cause and cardiovascular mortality. The underlying mechanisms may involve metabolic and inflammatory distress. Prospective studies are needed to further evaluate the potential clinical value of Gal-3BP.

    Soluble TWEAK and atheromatosis progression in patients with chronic kidney disease

    Circulating soluble TNF-like weak inducer of apoptosis (sTWEAK) concentrations are related to the presence of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, there are no data regarding the potential association between sTWEAK and atheromatosis progression in patients free of cardiovascular events.

    Fernández-Laso et al. measured soluble TWEAK serum concentration in 702 CKD patients without any previous cardiovascular event from The National Observatory of Atherosclerosis in Nephrology (NEFRONA) Study. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. The association between sTWEAK levels, atherosclerotic burden (number of plaques) and atheromatosis progression (increase in the number of plaques) after 24 months of follow-up was assessed.

    In the studied population, a continuous decrease in sTWEAK concentrations, with an increase in the number of atherosclerotic plaques after 24 months of follow-up, was observed. Multivariable linear regression analysis showed that age, blood pressure, HDL-c, and sTWEAK concentrations were independent predictors of atherosclerotic burden after 24 months of follow-up. In addition, sTWEAK concentrations diminished in CKD patients in whom progressive silent atherosclerosis was observed. Multivariable linear regression analysis showed that age, sex, smoking status and sTWEAK levels were independent predictors of atheromatosis progression after 24 months of follow-up.

    Lower sTWEAK concentrations are associated with atherosclerotic burden and atheromatosis progression in CKD patients free of clinical CVD. These data suggest that sTWEAK could serve as a biomarker to predict CV risk before clinical manifestations.

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