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Highlighted articles March

Volume 270 Issue March 2018

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

Atherosclerotic cardiovascular disease (ASCVD) is frequently confounded with other chronic diseases. Some of them, like diabetes, chronic kidney disease, or chronic inflammatory diseases have been recognized for long time as pathogenic drivers of ASCVD; others have been considered as innocent bystanders, for example because of shared risk factors like smoking or aging. As shown by several articles in this issue of Atherosclerosis, the coincidence of ASCVD with other diseases also opens avenues of finding novel pathomechanisms (and hence drug targets) and biomarkers, which may help improve the management of ASCVD.


Issue highlights



    Highlighted articles


    Cardiovascular disease in systemic lupus erythematosus is associated with increased levels of biomarkers reflecting receptor-activated apoptosis

    There is increasing evidence that mechanisms other than low-density lipoprotein (LDL)-driven inflammation are important in cardiovascular disease (CVD). Studies have shown that adaptive immune responses affect the development of atherosclerosis and thrombosis and several autoimmune diseases are associated with increased cardiovascular risk, suggesting that autoimmunity may contribute to CVD. However, our understanding of the underlying mechanisms remains limited. Wigren et al. investigated how biomarkers reflecting four aspects of autoimmunity (apoptosis, inflammation, tissue degradation and repair) associate with cardiovascular disease in subjects with systemic lupus erythematosus (SLE).

    The study included 484 well-characterized SLE patients, 69 with CVD (coronary artery disease, cerebrovascular disease or peripheral artery disease) and 253 controls. Occurrence of carotid plaques was investigated with ultrasound. Plasma levels of biomarkers reflecting apoptosis (Fas, TNF receptor 1, TRAIL receptor 2), inflammation (IL-6, IL-8, monocyte chemotactic protein-1), tissue degradation (matrix metalloproteinase (MMP)-1, MMP-3, MMP-7), and tissue repair (platelet-derived growth factor, epidermal growth factor and stem cell factor) were analyzed by Proximity Extension Assay.

    The results showed that subjects with SLE had markedly elevated plasma levels of biomarkers of apoptosis, inflammation and tissue degradation as compared to controls. SLE patients with CVD had higher levels of Fas, TNF receptor 1, TRAIL receptor 2, MMP-1 and -7 than those without CVD. The same associations were found for the presence of a carotid plaque. When controlling for the factors included in the Framingham risk score, all biomarkers except MMP-1 remained associated with the presence of a carotid plaque, while only TRAIL receptor 2 levels remained significantly associated with CVD.

    These findings suggest that the cardiovascular risk in SLE is associated with increased cell death by apoptosis and tissue degradation. Tissue injury rather than inflammation may be the cause of cardiovascular complications in autoimmune diseases such SLE.

    Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease

    Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbidity and mortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. Bozic at al. evaluated the association between OPG, OPN and sTWEAK and their combination with cardiovascular outcomes in CKD patients.
    The presence of calcified or non-calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA study. Patients were followed for cardiovascular outcomes, and OPG, OPN and sTWEAK serum levels were measured.

    At recruitment, 26% of CKD patients had VC. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut-off points had an adjusted higher risk of cardiovascular events. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events. A composite score of these three biomarkers increased the C-statistic and net reclassification index beyond conventional risk factors and VC.

    In conclusion, OPG, OPN and sTWEAK concentrations were associated with a higher prevalence of cardiovascular outcomes in CKD patients. The combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes.

    Low sleep quality is associated with progression of arterial stiffness in patients with cardiovascular risk factors: HSCAA study

    The importance of behavioral factors is increasingly recognized for prevention, development, and treatment of cardiovascular disease (CVD), as shown in epidemiological findings. Among these factors, improvement in sleep quality is considered to be a viable target for prevention and treatment of cardiovascular diseases. To gain insight into the underlying mechanisms, Kadoya et al. evaluated the significance of objectively measured sleep quality with regard to progression of arterial stiffness, over a 3-year follow-up period.

    This prospective cohort study included 306 serial patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. In addition to classical cardiovascular risk factors (body mass index, current smoking, past history of cardiovascular disease, dyslipidemia, diabetes mellitus), participants were examined for ambulatory blood pressure (BP), apnea-hypopnea index (AHI), standard deviation of the NN (RR) interval (SDNN) for heart rate variability (HRV), and objective sleep quality using actigraphy findings. Brachial-ankle pulse wave velocity at baseline and follow-up was considered as a parameter of arterial stiffness.

    Increases in PWV (%) were greater in the low sleep quality (LSQ) group compared to the normal sleep quality group. Patients with the greatest increase (≥20%) from baseline exhibited a significantly larger percentage of LSQ compared to those without PWV progression, with the association being significant even after adjustment for other clinical risk factors. Univariate logistic regression analyses showed that diabetes and LSQ were significantly associated with the greatest increase of PWV in all subjects. Comparison of characteristics among specific subgroups showed more prominent associations of LSQ with the greatest increase of PWV in patients with higher age, dyslipidemia, and higher AHI.

    Low sleep quality is a significant predictor of progression of arterial stiffness, independent of other cardiovascular risk factors.

    Risk of acute coronary syndrome and peripheral arterial disease in chronic liver disease and cirrhosis: A nationwide population-based study

    Cirrhosis represents the end stage of liver disease. No study so far has investigated the risk of acute coronary syndrome (ACS) and peripheral arterial disease (PAD) in cirrhosis. Lin et al. used the National Health Insurance Research Database (NHIRD), a population-based medical reimbursement system in Taiwan, to investigate the association between cirrhosis and risks of ACS and PAD.

    In this study included 57,214 patients diagnosed with cirrhosis between 2000 and 2010, identified from the Taiwan National Health Insurance claims data. Each patient was randomly selected and frequency-matched with an individual without cirrhosis by age, sex, and index year.

    The overall incidence rates of ACS and PAD were 2.81 and 2.97 per 1000 person-years, respectively, in the cirrhosis cohort. The cirrhosis cohort had a higher risk of ACS and PAD. In the cirrhosis cohort, the risk of ACS was highest among subjects with ascites.

    These data show that patients with chronic liver disease and cirrhosis have higher risks of ACS and PAD than those without.

    Alpha-1 antitrypsin deficiency: From the lung to the heart?

    Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have been little studied so far. Curjuric et al. aimed to shed further light on the potential role of A1AT deficiency in atherosclerosis and cardiovascular disease.

    Using data from 2614 adults from the population-based SAPALDIA cohort, the authors tested the association of serum A1AT levels and mutations in the SERPINA1 gene (encoding A1AT) with carotid intima-media thickness ((CIMT) measured by B-mode ultrasonography) or self-reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design. Mutations Pi-S and Pi-Z (Pi for protease inhibitor; S- and Z-alleles being functional single nucleotide polymorphisms) were coded as ordinal genotype score (MM, MS, MZ/SS, SZ and ZZ), according to their progressive biological impact.

    Serum A1AT concentration presented a U-shaped association with CIMT. At the lower end of the A1AT distribution, an analogous, linear association between SERPINA1 score and higher CIMT was observed, resulting in an estimated 1.2% increase in CIMT per unit. Genotype score was significantly associated with arterial hypertension with an odds ratio of 1.2 per unit. The association with cardiovascular disease was not significant.

    These results support a possible causal relationship between genetic A1AT deficiency and increased cardiovascular risk, which needs to be better taken into account for the management of affected patients and first-degree relatives.

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