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Highlighted articles June

Volume 273 Issue June 2018

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

High-density lipoproteins (HDL)

HDL cholesterol is a classical risk factor of atherosclerotic cardiovascular disease (ASCVD) whose pathogenic role and hence suitability as a therapeutic target are nowadays widely questioned because of negative outcomes of both randomized intervention studies and genetic Mendelian Randomization studies. However, HDL particles or quantitatively minor bioactive components of HDL rather than the cholesterol in HDL measured in clinical laboratories are mediating the anti-atherogenic properties of HDL. The elucidation of structure-function-disease relationships will be crucial to open novel avenues for testing the clinical utility of HDL. This issue of Atherosclerosis contains several articles addressing the functionality of HDL.

Valve disease

Calcific aortic valve disease (CAVD) is the most common valve disease worldwide and a major cause of morbidity and mortality in the elderly. The pathogenesis is not well understood and, as yet, no non-invasive therapy for prevention or cure is available. This issue of Atherosclerosis contains several articles on risk factors for the incidence and progression of CAVD as well as on animal models to investigate the pathogenesis of CAVD.

Issue highlights

Articles on High-density lipoproteins (HDL)

Articles on Valve disease

    Highlighted articles

    Novel association between CDKAL1 and cholesterol efflux capacity: Replication after GWAS-based discovery

    The importance of the functional properties of HDL is increasingly emphasized. However, studies on the genetic factors associated with HDL function are limited. Cheo et al.n aimed to identify genetic variants associated with an individual's cholesterol efflux capacity (CEC) using a genome-wide association study approach.

    A discovery group of 607 subjects with coronary artery disease and an independent replication group of 158 subjects were included in the analysis. CEC was assessed using macrophages loaded with radiolabeled cholesterol and ApoB-depleted serum. Genome-wide associations between the adjusted CEC and genotyped and imputed variants were examined with linear regression, assuming an additive genetic model. Adjustments were made for confounding parameters to assess the independence of associations and to determine R2 of overall model on CEC.

    The results show that 631 variants had significant association with CEC in the discovery group, and five of them correlated with CEC in the replication group. One was located near LOC541471 on 2q13, while the other four were located in CDKAL1 on 6p22.3. The association between the presence of any CDKAL1 variant and CEC was significant after adjustment for clinical and laboratory variables. High-density lipoprotein-cholesterol levels also showed a very significant association with CEC. Body mass index, current alcohol use, triglycerides levels, low-density lipoprotein-cholesterol levels and statin use showed borderline associations with CEC.

    AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE −/− mice

    ApoA-1 binding protein (AIBP) is a secreted protein that interacts with apoA-I and accelerates cholesterol efflux from cells. Zhang et al. recently reported that AIBP promotes apoA-1 binding to ABCA1 in the macrophage cell membrane, partially through amino acids 115–123. However, it is not clear whether AIBP regulates HDL production, reverse cholesterol transfer (RCT) and atherosclerosis in vivo.

    To test this hypothesis, apoE−/− mice with established atherosclerotic plaques were infected with recombinant adeno-associated virus 9 (rAAV) expressing human AIBP (rAAV-AIBP) or the protein lacking amino acids 115-123 (rAAV-AIBP(Δ115-123)), respectively.

    AIBP-treated mice showed reduction of atherosclerotic lesion formation, increase in circulating HDL levels and enhancement of reverse cholesterol transport to the plasma, liver, and feces. AIBP increased ABCA1 protein levels in the aorta and peritoneal macrophages. Furthermore, AIBP decreased atherosclerotic plaque macrophage content and the expression of chemotaxis-related factors. In addition, AIBP prevented macrophage inflammation by inactivating NF-κB and promoted the expression of M2 markers, like Mrc-1 and Arg-1. By contrast, lack of amino acids 115–123 in AIBP(Δ115-123) had no such preventive effects on the progression of atherosclerosis.

    This study shows that AIBP inhibits atherosclerosis progression and suggest it may be an effective target for prevention of atherosclerosis. These results, and the compelling evidence that AIBP decreases atherogenesis, are further discussed by M. Westerterp in her editorial.

    In conclusion, genetic variants associated with CEC were identified using a genome-wide association study-based approach. CDKAL1 variants showed correlations with CEC independent of HDL-cholesterol levels and other clinical characteristics.

    Myeloperoxidase modification of high-density lipoprotein suppresses human endothelial cell proliferation and migration via inhibition of ERK1/2 and Akt activation

    Preclinical studies have shown that HDL exert protective and reparative effects on the endothelium. HDL is, however, susceptible to oxidation, which affects its function. Myeloperoxidase (MPO)-induced modification of HDL results in loss of anti-apoptotic and anti-inflammatory functions, however, its effect on endothelial proliferation and migration has not been characterized. In this study, Chen et al. aimed to shed light on this effect.

    To this purpose, HUVECs were co-incubated with MPO-oxidised- or native-HDL (nHDL) in proliferation and migration assays. Signaling proteins were assessed by Western blots.

    nHDL caused dose-dependent increases of endothelial proliferation and migration. Consistent with an increase in cellular proliferation, HDL also stimulated proliferative cellular nuclear antigen (PCNA) expression and ERK phosphorylation in a concentration-dependent manner, which did not occur with MPO-oxidised HDL. HDL increased Akt phosphorylation, a driver of cellular migration. By contrast, MPO-oxidised HDL was unable to increase Akt phosphorylation and extensively-oxidised HDL even inhibited Akt phosphorylation.

    These results show that HDL promotes endothelial proliferation and migration, mediated in part via activation of ERK and Akt signalling. MPO-induced oxidative modification of HDL attenuates the endothelial-protective effects of HDL. These findings suggest that in an oxidative milieu, present in ageing and disease, HDL is likely to become ineffective. This has implications for HDL-raising therapies and emphasizes the need for strategies preventing oxidation-related HDL dysfunction.

    Resting heart rate and the incidence and progression of valvular calcium: The Multi-Ethnic Study of Atherosclerosis (MESA)

    Left-sided valvular calcification is associated with cardiovascular disease (CVD) morbidity and mortality. Resting heart rate (RHR) may influence valvular calcium progression through shear stress and is a vital sign underused for CVD risk assessment. Whether RHR, an established CVD risk factor, is associated with valvular calcium progression is unknown. Amoakwa et al. assessed whether RHR predicts incidence and progression of mitral annular calcium (MAC) and aortic valve calcium (AVC) in a community-based cohort free of CVD at baseline.

    The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study designed to investigate subclinical CVD in people without clinical CVD or atrial fibrillation at baseline. RHR was obtained from baseline electrocardiograms of 5498 MESA participants. MAC and AVC were quantified using Agatston scoring from cardiac computed tomography scans obtained at baseline and at a second examination at follow-up. Associations of RHR with incident MAC/AVC and annual change in MAC/AVC scores were examined, after adjusting for demographics, CVD risk factors, physical activity, and atrioventricular nodal blocker use.

    At baseline, participants had mean age of 62 ± 10 years and mean RHR of 63 ± 10 bpm; 12.3% and 8.9% had prevalent AVC and MAC, respectively. Over a median of 2.3 years, 4.1% and 4.5% developed incident AVC and MAC, respectively. Each 10 bpm higher RHR was significantly associated with incident MAC, but not incident AVC. However, RHR was associated with AVC progression but not MAC progression.

    Higher RHR was associated with MAC incidence and AVC progression, independent of traditional CVD risk factors and was stronger for men and older adults. Future studies are needed to determine whether modification of RHR through lifestyle or pharmacologic interventions can reduce valvular calcium incidence or progression.

    Serum magnesium, phosphorus, and calcium levels and subclinical calcific aortic valve disease: A population-based study

    Subclinical early stage of CAVD is characterized by aortic valve calcification (AVC). Although micronutrients are known to contribute to cardiovascular disease, their relationship with CAVD remains poorly evaluated. Hisamatsu et al. examined the association of serum levels of magnesium, phosphorus, and calcium with prevalence, incidence, and progression of aortic valve calcification (AVC). They conducted a prospective study in a population-based sample of Japanese men aged 40–79 years without known cardiovascular disease and chronic kidney disease at baseline, and quantified AVC from serial computed tomographic images with the Agatston method.

    AVC prevalence was observed in 173 of 938 participants at baseline and AVC incidence was observed in 138 of 596 participants without baseline AVC at follow-up. After adjustment for demographics, behaviors and cardiovascular risk factors, relative risks in the highest versus lowest categories of serum magnesium, phosphorus, and calcium were 0.62, 1.45, and 1.43, respectively, for AVC prevalence and 0.62, 1.93, and 1.09, respectively, for AVC incidence. Their linear trends of serum magnesium and phosphorus were also all statistically significant. In 131 participants with baseline AVC, there was no association of any serum micronutrients with AVC progression.

    Serum magnesium was inversely associated, while serum phosphorus was positively associated with AVC prevalence and incidence, suggesting that these serum micronutrients may be potential candidates for risk prediction or prevention of CAVD, and warranting further studies.


    Progression of calcific aortic valve sclerosis in WHHLMI rabbits

    The pathogenesis of aortic valve calcification remains largely unknown, primarily due to the lack of an adequate animal model. The high-cholesterol diet-induced AS model in rabbits is one of the established models, but it has the significant limitation of liver dysfunction leading to low survival rates. Hara et al. hypothesized that the myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbit, an animal model of familial hypercholesterolemia and atherosclerosis, could be a useful animal model of AS.

    To test this hypothesis, WHHLMI rabbits, aged 20 months and 30 months, and control Japanese White rabbits, aged 30 months, were subject to echocardiography under anesthesia. Histological evaluation of the aortic valves and quantitative assessment of calcification-related molecules by RT-PCR were also performed.

    The lipid profile was similar between 20-month and 30-month rabbits. Two rabbits died due to spontaneous myocardial infarction during the study. Thirty-months-old WHHLMI rabbits exhibited significantly smaller aortic valve area and higher maximal transvalvular pressure gradient than 20 month-old rabbits. Macroscopic examination of excised aortic valves demonstrated thickened and degenerated valve leaflets at 30 months. Histological evaluation confirmed thickened leaflets with calcified nodules at 30 months. Real-time PCR of resected aortic valve also showed increased expression levels of calcification-related molecules including osteopontin, Sox9, Bmp2, RANKL, osteoprotegerin, and Runx2 in 30-month-old rabbits.

    These data indicate the WHHLMI rabbits can be used as animal models of AS without a high-cholesterol diet or vitamin D supplements.

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