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Highlighted articles January

Volume 268 Issue January 2018

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

The success of intensified LDL cholesterol lowering with anti-PCSK9 antibodies or anti-inflammatory treatment with an antibody against IL1beta receptor has opened the arena for treatment of residual cardiovascular risk with biologicals. The clinical efficacy of other novel anti-atherosclerotic treatments with antibodies, antisense oligonucleotides, and small interfering RNAs is currently investigated in phase 3 trials. These novel drugs are or will be much more expensive than current state of the art treatment with statins, blood pressure lowering drugs, and anti-thrombotic drugs. It will not be cost-effective to treat all patients who do not reach target values defined with these novel drugs. As a consequence, and to enable personalized treatment, we will need biomarkers that help sub-stratify cardiovascular risk in patients, who by current guidelines are collectively defined to be at high or very high risk, for example patients with established atherosclerotic cardiovascular disease, diabetes or familial hypercholesterolemia, or multiple risk factors. This issue of Atherosclerosis contains several articles on studies addressing this need by assessing the presence or severity of ASCVD with imaging.


Issue highlights



    Highlighted articles


    A spectrum of retinal vasculature measures and coronary artery disease

    Cardiovascular disease (CVD) is a leading cause of mortality and morbidity. Most research on CVD has been focused on larger vessels (coronary arteries) contributing to the development of coronary artery disease (CAD). However, it has been increasingly recognised that coronary microvascular changes may also play a significant role in CAD pathogenesis. Wang et al. aimed to comprehensively describe a spectrum of retinal vessel measures including fractal dimension (Df) and their associations with indices of coronary artery disease (CAD) extent and severity, as well as hypertension and diabetes.


    The Australian Heart Eye Study (AHES) is an observational study that surveyed 1680 participants presenting to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. A range of novel retinal vessel geometric measures (Df, curvature tortuosity, and branching angle) was quantified in retinal photographs using semi-automated software, the Singapore ‘I’ Vessel Assessment (SIVA) tool. A combined retinal score was constructed, aiming to assess the joint effect of multiple retinal vessel parameters on CAD, comprising of those variables that were most strongly significant upon multivariate analysis - Df, arteriolar curvature tortuosity, and retinal arteriolar calibre. CAD was quantified using measures obtained from coronary angiography.


    A total of 1187 participants had complete data on retinal vessel measurements and coronary vessel evaluation. Retinal vascular Df and curvature tortuosity decreased with increasing age; women had significantly lower Df than men. Straighter retinal vessels were associated with CAD extent and Gensini scores in multivariable analysis. Accounting for media opacity by sub-group analysis in pseudophakic patients, the combined retinal score was associated with stenosis greater than 50% in any coronary artery segment (vessel score) and obstructive coronary stenosis in all three main coronary arteries (segment score). Lower Df and narrower arteriolar branching angle were associated with CAD vessel score. In sex-stratified multivariate analyses, straighter arterioles were associated with greater odds of CAD in men, and narrower venular branching angle was associated with CAD in women.


    In conclusion, several retinal vessel measures were associated with CAD extent and severity. A sparser retinal microvascular network (smaller Df) was associated with older age and female gender. After accounting for the impact of media opacity, retinal vessel measures were associated with more diffuse and severe CAD.


    Reliability of oscillometric central blood pressure responses to lower limb resistance exercise

    The inclusion of low intensity resistance training (RT) into both primary and secondary cardiovascular disease-prevention programs is associated with positive cardiovascular effects. However, it remains underutilized as a rehabilitation tool as there is no reliable way to monitor the additional stress placed on the central organs. In this study, Fryer et al. aimed to determine between-day reliability of central haemodynamic indices using oscillometric pulse wave analysis (PWA) during progressive sub-maximal RT.

    Nineteen healthy young males were tested on three different mornings in a fasted state. Central hemodynamic variables, including augmentation index (AIx), AIx normalized to a heart rate of 75 beats per minute (AIx@75), central systolic blood pressure (cSBP), forward (Pf) and backward (Pb) wave reflection were measured at rest, as well as during leg extension RT at 10, 15 and 20% of maximal volitional contraction (MVC), and following 1 min and 5 min passive recovery.

    During RT at 10, 15 and 20% MVC, the intraclass correlation coefficient (ICC) values for AIx@75, cSBP, Pf and Pb exceeded the criteria for excellent reliability. During the 5 min recovery, the ICC values for AIx@75, cSBP, Pf and Pb indicated good to excellent reliability.

    Central blood pressure can be reliably determined during and following resistance training using oscillometric technology. The PWA device holds potential for advancing resistance training prescription guidelines in patients with overt cardiovascular diseases.

    Thrombogenicity and central pulse pressure to enhance prediction of ischemic event occurrence in patients with established coronary artery disease: The MAGMA-ischemia score

    Thrombogenicity and vascular stiffness are independent predictors of adverse cardiovascular events. Cardiovascular risk estimators for patients with coronary artery disease (CAD) do not include markers of thrombogenicity and vascular stiffness. Bliden et al. aimed to develop a clinical and biomarker score to predict 3-year adverse cardiovascular events in patients with documented CAD.

    Four-hundred-eleven patients, undergoing coronary angiography, with an ejection fraction ≥40% and angiographically documented severe coronary artery stenosis were included in this sub-study of the Multi-Analyte, thrombogenic, and Genetic Markers of Atherosclerosis (MAGMA) study (a prospective cohort study of patients undergoing elective cardiac catheterization to identify novel biomarkers associated with atherosclerosis extent and predict future occurrence of cardiovascular events). Thrombelastography indices and central pulse pressure (CPP) were determined at the time of catheterization.

    Predictors of death, myocardial infarction (MI) or stroke were identified, and a numerical ischemia risk score was developed. The primary endpoint of cardiovascular death, MI or stroke occurred in 22 patients. The factors associated with events were age, prior percutaneous coronary intervention or coronary artery bypass grafting, diabetes, CPP, and thrombin-induced platelet-fibrin clot strength, and were included in the MAGMA-ischemia score. The MAGMA-ischemia score showed a c-statistic of 0.85. Patients with MAGMA-ischemia score greater than 5 had highest risk to develop clinical events. When compared to previous models, the MAGMA-ischemia score yielded a higher discrimination.
    The results indicate that inclusion of CPP and assessment of thrombogenicity in a novel score for patients with documented CAD enhance the prediction of future events.

    Brachial artery diameter as a marker for cardiovascular risk assessment: FMD-J study

    Measurement of flow-mediated vasodilation (FMD) in the brachial artery using high-resolution ultrasound is widely used as a method for the assessment of endothelial function in clinical practice. Baseline brachial artery (BBA) diameter has been reported to be a potential confounding factor of FMD. In this study, Maruhashi et al. evaluated the relationships between BBA diameter and cardiovascular risk factors and compared the diagnostic accuracy of BBA diameter with that of FMD, in subjects without cardiovascular risk factors and patients with cardiovascular disease (CVD).

    BBA diameter and FMD were measured in 5695 male subjects from the FMD-J study and the Flow-mediated Dilation Japan Registry study (FDR study). In addition, the incidence of cardiovascular events was retrospectively investigated in a sample of 440 male subjects (undergoing health-screening examinations at Hiroshima University), to compare the accuracy of BBA diameter with that of FMD in predicting cardiovascular events.

    BBA diameter and FMD significantly correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose as well as Framingham risk score. The prevalence of cardiovascular risk factors and CVD increased with the increase in BBA diameter and FMD. Area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for BBA diameter to diagnose subjects without cardiovascular risk factors or patients with CVD was significantly lower than that for FMD. In the retrospective study, the AUC value of the ROC curve for BBA diameter to predict first major cardiovascular events was significantly lower than that of FMD.

    The results suggest that in men diagnostic accuracy of BBA diameter for CV risk is inferior to that of FMD.

    Additional prognostic value of brachial-ankle pulse wave velocity to coronary computed tomography angiography in patients with suspected coronary artery disease

    Artery stiffens is the result of the aging process and atherosclerosis. Increased arterial stiffness is associated with a higher risk of future cardiovascular events, therefore, its measurement provides some unique prognostic information about future risks. Brachial-ankle pulse wave velocity (baPWV) is a reliable and non-invasive measure of arterial stiffness. Hwang et al. aimed to investigate whether information about arterial stiffness provides additional prognostic value to coronary computed tomography angiography (CCTA) findings.

    523 consecutive patients with suspected coronary artery disease (CAD), who underwent CCTA and baPWV measurement within a month, were retrospectively analyzed. A composite of cardiovascular death, nonfatal myocardial infarction (MI), coronary revascularization, nonfatal stroke, and hospitalization for cardiovascular causes was assessed.

    During a median follow-up of 43.9 months, the composite endpoint occurred in 66 patients. After adjustment for clinical risk factors and CCTA findings, higher baPWV was an independent prognostic factor for the composite endpoint. The addition of baPWV to clinical risk factors and CCTA findings significantly improved the prediction of cardiovascular events.

    The results show that arterial stiffness provides additional prognostic information to CCTA findings in patients with suspected CAD. baPWV can be a useful tool for risk stratification in this population.

    Arterial inflammation measured by 18F-FDG-PET-CT to predict coronary events in older subjects

    18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) has been used in the diagnosis of malignant diseases and is a potentially useful imaging tool for the quantitative evaluation of systemic inflammation. In addition, combining images obtained via 18F-FDG-PET with computed tomography (CT) images can provide localize vascular inflammation. This implies that 18F-FDG-PET-CT may be able to detect early atherosclerotic changes that cannot be identified otherwise. Indeed, a few studies have shown that FDG uptake may predict future adverse cardiovascular events; however, its predictive role for prognosis in older subjects has not been elucidated so far. In this study, Iwatsuka et al. tested the prognostic value of aortic inflammation detected via 18F-FDG-PET-CT in older subjects.

    The authors retrospectively evaluated 309 subjects aged over 65 years, without a history of overt coronary artery disease, who underwent 18F-FDG-PET-CT. Target-to-background ratio (TBR) was calculated at the ascending aorta. The endpoint was occurrence of coronary heart disease (CHD) events.
    The highest TBR tertile was associated with a high CHD event rate, accounting for death due to non-CHD causes as a competing risk. In a Fine and Gray competing risk proportional hazard regression model, TBR was associated with significantly high CHD events independently of the Framingham risk score (FRS). Moreover, TBR exhibited predictive capacity for CHD events that was additive to that yielded by the FRS.

    In older subjects with no history of malignant disease or overt coronary artery disease, arterial inflammation evaluated by FDG uptake provides information on future occurrence of coronary artery events.

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