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Highlighted articles February

Volume 257 Issue February 2017

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

Deposits of calcium are a hallmark of advanced atherosclerosis. This issue of Atherosclerosis contains several articles, which report on the prognostic value of calcium imaged in atherosclerotic lesion or the calcium homeostasis regulating hormone vitamin D as well as the regulation of calcium homeostasis in vascular smooth muscle cells.

Issue highlights


    Highlighted articles

    Is there a role for coronary artery calcification scoring in primary prevention of cerebrovascular disease?

    Cerebrovascular disease (CVA) is one of the most prevalent causes of death and disability in the United States, and its primary prevention is crucial. It is recommended that all adults should undergo an office-based traditional risk assessment using established predictive models, such as the Framingham Stroke Profile Score or the atherosclerotic cardiovascular disease (ASCVD) risk calculator from the American College of Cardiology/American Heart Association (ACC/AHA).

    Coronary artery calcification (CAC) is an independent risk predictor of cardiovascular disease (CVD), which often includes CVA. A CAC score can improve discrimination for CVD in the general population beyond established risk prediction tools. Several recent major prospective studies have assessed the use of CAC data to predict CVA events in asymptomatic patients. The CAC score itself is a reliable independent risk factor for predicting CVA events after adjusting for traditional risk factors. Regarding the discriminative value, there is little value afforded by the addition of the CAC score to current CVA risk prediction tools.

    In this review, Osawa et al. summarize the current key literature regarding CAC score and CVA. The authors focus on its diagnostic value in identifying patients at risk and on its utility for stratification of individuals.

    Thoracic aortic calcium, cardiovascular disease events, and all-cause mortality in asymptomatic individuals with zero coronary calcium: The Multi-Ethnic Study of Atherosclerosis (MESA)

    Thoracic aortic calcium (TAC) is associated with incident cardiovascular disease (CVD) and all-cause mortality. Nevertheless, the independent 10-year prognostic value of TAC in individuals with coronary artery calcium (CAC) = 0, beyond traditional risk factors, is not well established.

    Kim et al. followed 3415 Multi-Ethnic Study of Atherosclerosis (MESA) participants with baseline CAC = 0. TAC was measured in the ascending and descending aorta and quantified using the Agatston score. Multivariable Cox proportional hazards regression models were used to study the association between TAC and incident CHD, CVD events, and all-cause mortality. Likelihood ratio tests were used to compare prediction models, including traditional risk factors plus TAC, with risk factors alone.

    The results showed that 406 participants had TAC>0 at baseline. Over a median follow-up of 11.3 years, unadjusted event rates per 1000 person-years were higher in TAC>0 than in TAC = 0 participants. However, in multivariable Cox regression analyses adjusting for CVD risk factors, neither TAC>0, TAC>100 nor log(TAC+1) was independently associated with any of the study outcomes, nor improved their prediction compared to traditional risk factors alone.

    In conclusion, in a multi-ethnic, modern US population of asymptomatic individuals with CAC = 0 at baseline, the prevalence of TAC>0 was low, and TAC did not improve the 10-year estimation of prognosis beyond traditional risk factors. Therefore, this study suggests that in the presence of CAC = 0, TAC measurement is unlikely to provide sufficient additional prognostic information to further improve risk assessment.

    In their editorial, Erbel and Churzidse further comments on the results of the present study and recent publications demonstrating that TAC analysis does not improve risk prediction beyond what is known for CAC, even in subjects with CAC = 0.

    Association of tobacco use and cessation with coronary atherosclerosis

    The impact of tobacco use and cessation on atherogenesis remains unclear. Cheezum et al. aimed to study the association of tobacco use and prior cessation with the presence, extent, and severity of atherosclerosis on coronary computed tomographic angiography (CTA).

    The authors examined 1798 consecutive symptomatic patients, without known coronary artery disease (CAD), referred for CTA, stratified by smoking status (never, current [within 30 days], or former [>30 days before CTA]). Plaque severity (none, <50%, ≥50% stenosis), composition (non-calcified, partially calcified, or calcified plaque), and segment involvement score (SIS) were visually graded. Multivariate analysis was performed adjusting for CAD risk factors and cholesterol lowering medication use.

    The median age of patients was 50 years, with 74% never smokers, 12% current smokers, and 14% former smokers. Smoking exposure in former versus current smokers was 11 and 10 pack-years, respectively. Compared to never smokers, current smokers demonstrated an increased odds ratio of all plaque types, non-obstructive CAD, obstructive CAD, and SIS > 4. Compared to current smoking, prior smoking cessation (≥12 years) was associated with a decreased odds ratio of any non-calcified plaque, calcified plaque, and obstructive CAD.

    The results demonstrate that current smoking is independently associated with the presence and extent of coronary plaque, and a higher risk of non-obstructive and obstructive CAD compared to never smoking. Moreover, prior smoking cessation correlates with improvements in CTA-identified plaque measures.

    In their editorial, Gambardella et al. emphasize the fact that despite the clinical evidence that smoking exposure has a dose dependent association with the presence of extensive and calcified atherosclerotic plaques, the molecular mechanisms and cellular responses underlying the relationship between smoke and atherosclerosis are not fully understood. Nevertheless, they describe how smoking can affect each single stage of the atherosclerotic disease: (1) endothelial damage/activation; (2) endothelial interaction with monocyte and their recruitment; (3) formation of foam cells with genesis of the lipid core, and fibrous cap of the plaque; (4) plaque vulnerability and eventual destabilization and rupture.

    Serum 25-hydroxyvitamin D is associated with incident peripheral artery disease among white and black adults in the ARIC study cohort

    Low 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with peripheral artery disease (PAD). Prevalence of low 25(OH)D and PAD differ between whites and blacks. However, these associations have not been studied prospectively or in a population-based cohort. Rapson et al. tested the hypothesis that low 25(OH)D levels are associated with greater risk of incident PAD in white and black adults.

    The authors followed, for incident PAD events, 11,789 Atherosclerosis Risk in Communities (ARIC) participants, free of PAD at visit 2, through 2011. 25(OH)D levels were measured in serum collected at ARIC visit 2 (1990–1992). 25(OH)D (ng/ml) was categorized as deficient (<20), insufficient (20 to <30) or sufficient (≥30). PAD was defined by an ankle brachial index (ABI) of <0.9 at ARIC visits 3 or 4 or a hospital diagnosis with an ICD-9 code, indicating PAD during follow-up. Multivariable-adjusted Cox proportional hazards regressions were used for the analysis.

    Over a mean follow-up of 17.1 years, 1250 incident PAD events were identified. 22% of whites and 61% of blacks were 25(OH)D deficient. After adjustment for demographic characteristics, the hazard ratio of PAD in participants with deficient versus sufficient 25(OH)D was 1.49. Inclusion of BMI, physical activity, and smoking status attenuated the association. The association between 25(OH)D and PAD was qualitatively stronger in blacks.

    In conclusion, the study shows that deficient 25(OH)D was associated with increased risk of PAD in black and white participants. Whether treatment of low vitamin D through supplementation or modest sunlight exposure prevents PAD is unknown.

    The P2Y2 nucleotide receptor is an inhibitor of vascular calcification

    Mutations in the 5'-nucleotidase ecto (NT5E) gene encoding CD73, a nucleotidase that converts AMP to adenosine, are associated with arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood.

    Qian et al. assessed whether extracellular nucleotides acting via the P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. The authors used apolipoprotein E, P2Y2R double knockout mice (ApoE−/−P2Y2R−/−) to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) from P2Y2R−/− mice, grown in high phosphate medium, were used to investigate the role of P2Y2R in the conversion of these cells into osteoblasts. In addition, the effect of P2Y2R on the transcriptional activity of Runx2 was analysed by luciferase-reporter assays.

    The results show that P2Y2R deficiency in ApoE−/− mice caused extensive intimal calcification, despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase, that degrades nucleoside di- and triphosphates, accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter-driven luciferase reporter gene.

    In conclusion, this study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of VSMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.

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