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Highlighted articles August

Volume 251 Issue August 2016

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

Issue highlights

    Review article

    Non-invasive imaging of atherosclerosis regression with magnetic resonance to guide drug development

    Slowing of progression and inducing regression of atherosclerosis with medical therapy have been shown to be associated with an extensive reduction in risk of cardiovascular events. This proof of concept was obtained with invasive angiographic studies, but these are impractical for sequential investigations.

    Non-invasive imaging has henceforth replaced the more cumbersome invasive studies and has proven extremely valuable in numerous occasions. Because of excellent reproducibility and no radiation exposure, magnetic resonance imaging (MRI) has become the non-invasive method of choice to assess the efficacy of anti-atherosclerotic drugs. The high accuracy of this technology is particularly helpful in rare diseases where the small number of affected patients makes the conduct of outcome-trials in large cohorts impractical. With MRI it is possible to assess the extent, as well as the composition of atherosclerotic plaques, further enhancing the utility of this technology.

    In this review, Raggi and colleagues discuss the state of the art of MRI for vascular imaging, with a specific focus on its implementation in the process of drug development. Magnetic resonance imaging can provide information on the location, extent and composition of atheromatous plaques in peripheral arterial beds and has been used in numerous trials to study regression of atherosclerosis. However, to date MRI has demonstrated no utility to image coronary artery atherosclerotic plaques.

    Highlighted articles

    Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α

    Vascular calcification is prevalent in clinical states characterized by low-grade chronic inflammation, such as chronic kidney disease (CKD).

    Calciprotein particles (CPP) are calcium phosphate-containing nano-aggregates, which have been found in the blood of CKD patients and appear pro-inflammatory in vitro.

    Aghagolzadeh et al. assessed the interplay of CPPs and inflammatory cytokines with regard to the calcification of vascular smooth muscle cells (VSMC).

    To this purpose, primary or secondary CPP were generated using phosphate-enriched culture medium at 37°C. Human VSMC were cultured in this medium and mineralization was measured. Expression of TNF-α was quantified by qPCR, ELISA and Western blot in calcified VSMC. To further characterize the role of TNF-α and its receptors in the calcification of VSMC, RNAi experiments using siTNF-α, siTNFR1 and siTNFR2 were performed.

    The authors showed that addition of phosphate to cell culture medium led to the rapid formation of primary CPP, which underwent spontaneous transformation to secondary CPP. Exposure of VSMC to secondary CPP led to pronounced and concentration-dependent calcification, whereas exposure to primary CPP did not.

    Importantly, secondary CPP induced oxidative stress, and led to the upregulation and release of TNF-α.

    Addition of TNF-α to the cell culture medium enhanced calcification, whereas suppression of endogenous TNF-α or TNF receptor type 1 (TNFR1) expression by siRNA, ameliorated calcification.

    Taken together, the results indicate that secondary, but not primary CPP, induce VSMC calcification. Secondary CPP induce expression and release of TNF-α, which enhances calcification via its TNFR1 receptor.

    In his commentary, P. Sage highlights how this study represents another important step in bringing together the understanding of inflammatory and stress-related, osteogenic and physiochemical processes that are key to vascular calcification.

    Lineage tracing of cells involved in atherosclerosis

    Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis.

    Albarrán-Juárez et al. aimed at identifying the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions.

    The authors combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis.

    They found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68+ cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2), and vascular cell adhesion molecule (Vcam1), as well as increased mRNA levels of genes related to matrix synthesis, such as Col1a2 and Fn1, than non SM-derived CD68+ cells.

    In conclusion, these results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression.

    In their commentary, I. Bot and J. Kuiper emphasize how this study provides convincing evidence of a certain degree of cellular plasticity within the atherosclerotic plaque, showing macrophage-like cells that have differentiated from smooth muscle cells and vice versa, adding further insights into the understanding of cellular processes during atherosclerotic lesion progression.

    Combined effects of exercise capacity and coronary atherosclerotic burden on all-cause mortality in asymptomatic Koreans

    Both exercise capacity and coronary artery calcium score (CACS) are important prognostic factors in cardiovascular outcome. Yet, whether there is a significant interaction between these two factors in influencing clinical outcome is still uncertain.

    Choi et al. investigated the combined effects of exercise capacity and CACS on all-cause mortality in an asymptomatic population.

    To this aim, a retrospective cohort of 25,972 asymptomatic subjects (from a multicenter registry of health screening), who underwent both CACS and treadmill exercise test, was included in the final dataset for analysis. Outcome was defined as all-cause mortality, obtained from the national mortality registry.

    The mean age of the study subjects was 53.7±7.7 years, 81.5% of them were males. Median follow-up duration was 5.5 years and 226 cases of all-cause mortality occurred.

    The authors showed that, in multivariate Cox’s proportional hazard model with interaction term, exercise capacity ≥10 METs and CACS ≥400 were significant predictors of all-cause mortality.

    In patients with higher exercise capacity, the effect of high CACS on all-cause mortality was significantly smaller than in those with lower exercise capacity. In subjects with lower exercise capacity, the HR for all-cause mortality of CACS ≥400 was estimated to be about three times of that in subjects with higher exercise capacity, after adjustment for age, gender, fasting glucose, creatinine, alanine transaminase and albumin.

    In the asymptomatic population, the effect of high CACS on all-cause mortality was lessened by good exercise capacity.

    In conclusion, the authors suggested that good physical fitness may reduce the adverse effect of high coronary atherosclerotic burden.

    In their commentary, S Endes and A. Schmidt-Trucksäss explain how this finding is of interest especially for risk stratification of asymptomatic persons at intermediate risk. In those persons, exercise stress testing may provide further useful information for individual cardiovascular risk management, which may lead to a more adapted risk factor control therapy either to a more aggressive lifestyle intervention or an adaptation of medication treatment or a combination of both.

    Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial

    Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes.

    With this secondary analysis, Albers et al. aimed to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes.

    To this purpose, individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day. In both groups, ezetimibe was added as needed to maintain an on-treatment LDL-C in the range of 40–80 mg/dL. The primary composite endpoint was death from coronary disease, non-fatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization.

    HDL-C, HDL3-C, sdLDL-C and LDL-TG were measured at baseline by detergent-based homogeneous assays. HDL2-C was computed by the difference between HDL-C and HDL3-C.

    Analyses were performed on 3094 study participants already on statin therapy prior to enrollment in the trial. Independent contributions of lipoprotein fractions to CV events were determined by Cox proportional hazards modeling.

    The authors showed that baseline HDL3-C was protective against CV events while HDL-C, HDL2-C, sdLDL-C and LDL-TG were not event-related.

    The results of this secondary analysis of the AIM-HIGH study indicate that levels of HDL3-C, but not other lipoprotein fractions, are predictive of CV events, suggesting that the HDL3 subclass may be primarily responsible for the inverse association of HDL-C and CV disease.

    In his commentary, R. McGarrah highlights the importance of this study to relate HDL size, structure, composition and function with clinical outcomes of CV, with the aim of refining the utility of this lipoprotein in the treatment of the world’s deadliest disease.

    HDL mimetic CER-001 targets atherosclerotic plaques in patients

    Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate, in part, to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans.

    Zheng et al. analyzed the delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients.

    CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 (89Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of 89Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001.

    The authors showed that, one hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL, with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8%.

    As assessed by PET/CT imaging, arterial uptake of CER-001, expressed as target-to-background ratio (TBRmax), increased significantly 24 h after infusion, and remained high up to 48 h. TBRmax was higher in plaque compared with non-plaque segments. Moreover, by CE-MRI, plaque TBRmax correlated with local plaque contrast enhancement.

    Infusion of the HDL mimetic CER-001 increased plasma apoA-I concentration and plasma cholesterol efflux capacity.

    The authors suggested that these results support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis.

    Strenghts and limitations of the study are further reviewed in the commentary by Chatzizisis et al.

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