Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Non-contrast short MRI surveillance for HCC screening: the study protocol of the SMS-HCC prospective multicenter study.

Hepatocellular carcinoma (HCC) comprises 75 to 85% of all primary liver cancers. Current guidelines recommend a biannual HCC surveillance using ultrasound (US) for high-risk patients. However, due to its low sensitivity for detection of early-stage HCC lesions, there is an urgency for more sensitive surveillance tools. Here, we describe the potential of a short MRI surveillance (SMS) protocol for HCC, including axial T1-weighted in-out phase, fat-saturated T2-weighted, and diffusion-weighted sequences. In this prospective, multicenter, patient cohort study, patients will be recruited from existing HCC surveillance cohorts of six medical centers in The Netherlands. Surveillance patients who undergo biannual US, will be invited for SMS on the same day for 3 years. In case of a suspicious finding on either US or SMS, patients will be invited for a full MRI liver protocol including gadolinium-based contrast agent intravenous injection within 2 weeks. To our knowledge, this will be the first study to perform a head-to-head comparison with a paired US-MRI design. We hypothesize that the sensitivity of SMS for detection of early-stage HCC will be higher than that of US leading to improved survival of surveillance patients through timely HCC diagnosis. Furthermore, we hypothesize that the SMS-HCC protocol will prove cost-effective.Relevance statement The US sensitivity for detecting early-stage HCC has been reported to be less than 50%. We expect that the proposed SMS will detect at least twice as many early-stage HCC lesions and therefore prove to be cost-effective. Key points • The low sensitivity of US necessitates better imaging tools for HCC screening.• This is the first study with a paired US-MRI design.• This design will allow a head-to-head comparison in both diagnostics and patient-acceptance.• We expect that SMS can contribute to a higher survival rate.

Thin slice photon-counting CT coronary angiography compared to conventional CT: Objective image quality and clinical radiation dose assessment.

BACKGROUND: Photon-counting CT (PCCT) is the next-generation CT scanner that enables improved spatial resolution and spectral imaging. For full spectral processing, higher tube voltages compared to conventional CT are necessary to achieve the required spectral separation. This generated interest in the potential influence of thin slice high tube voltage PCCT on overall image quality and consequently on radiation dose. PURPOSE: This study first evaluated tube voltages and radiation doses applied in patients who underwent coronary CT angiography with PCCT and energy-integrating detector CT (EID-CT). Next, image quality of PCCT and EID-CT was objectively evaluated in a phantom study simulating different patient sizes at these tube voltages and radiation doses. METHODS: We conducted a retrospective analysis of clinical doses of patients scanned on a conventional and PCCT system. Average patient water equivalent diameters for different tube voltages were extracted from the dose reports for both EID-CT and PCCT. A conical phantom made of polyethylene with multiple diameters (26/31/36 cm) representing different patient sizes and containing an iodine insert was scanned with a EID-CT scanner using tube voltages and phantom diameters that match the patient scans and characteristics. Next, phantom scans were made with PCCT at a fixed tube voltage of 120 kV and with CTDIVOL values and phantom diameters identical to the EID-CT scans. Clinical image reconstructions at 0.6 mm slice thickness for conventional CT were compared to PCCT images with 0.4 mm slice thickness. Image quality was quantified using the detectability index (d'), which estimated the visibility of a 3 mm diameter contrast-enhanced coronary artery by considering noise, contrast, resolution, and human visual perception. Alongside d', noise, contrast and resolution were also individually assessed. In addition, the influence of various kernels (Bv40/Bv44/Bv48/Bv56), quantum iterative reconstruction strengths (QIR, 3/4) and monoenergetic levels (40/45/50/55 keV) for PCCT on d' was investigated. RESULTS: In this study, 143 patients were included: 47 were scanned on PCCT (120 kV) and the remaining on EID-CT (74 small-sized at 70 kV, 18 medium-sized at 80 kV and four large-sized at 90 kV). EID-CT showed 7%-17% higher d' than PCCT with Bv40 kernel and strength four for small/medium patients. Lower monoenergetic images (40 keV) helped mitigate the difference to 1%-6%. For large patients, PCCT's detectability was up to 31% higher than EID-CT. PCCT has thinner slices but similar noise levels for similar reconstruction parameters. The noise increased with lower keV levels in PCCT (≈30% increase), but higher QIR strengths reduced noise. PCCT's iodine contrast was stable across patient sizes, while EID-CT had 33% less contrast in large patients than in small-sized patients. CONCLUSION: At 120 kV, thin slice PCCT enables CCTA in phantom scans representing large patients without raising radiation dose or affecting vessel detectability. However, higher doses are needed for small and medium-sized patients to obtain a similar image quality as in EID-CT. The alternative of using lower mono-energetic levels requires further evaluation in clinical practice.

Coffee consumption is associated with a reduced risk of colorectal cancer recurrence and all-cause mortality.

Coffee consumption has been associated with a reduced risk of developing colorectal cancer (CRC). However, it is not clear whether coffee consumption is related to CRC progression. Hence, we assessed the association of coffee consumption with CRC recurrence and all-cause mortality using data from a prospective cohort study of 1719 stage I-III CRC patients in the Netherlands. Coffee consumption and other lifestyle characteristics were self-reported using questionnaires at the time of diagnosis. We retrieved recurrence and all-cause mortality data from the Netherlands Cancer Registry and the Personal Records Database, respectively. Cox proportional hazard regression models with and without restricted cubic splines were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, education, smoking status, cancer stage and tumor location. We observed 257 recurrences during a 6.2-year median follow-up and 309 deaths during a 6.6-year median follow-up. Consuming more than 4 cups/d of coffee compared to an intake of <2 cups/d was associated with a 32% lower risk of CRC recurrence (95% CI: 0.49, 0.94,). The association between coffee consumption and all-cause mortality was U-shaped; coffee intake seemed optimal at 3-5 cups/d with the lowest risk at 4 cups/d (HR: 0.68, 95% CI: 0.53, 0.88). Our results suggest that coffee consumption may be associated with a lower risk of CRC recurrence and all-cause mortality. The association between coffee consumption and all-cause mortality appeared nonlinear. More studies are needed to understand the mechanism by which coffee consumption might improve CRC prognosis.

Progression of arterial calcifications: what, where, and in whom?

OBJECTIVES: There is a lack of information on the development of arteriosclerosis over time. This study aims to assess long-term sex-specific changes in arterial calcifications in five arteries, and the influence of cardiovascular risk factors hereon. METHODS: From a population-based cohort, 807 participants (mean baseline age, 65.8; SD, 4.2) underwent a non-contrast computed tomography (CT) examination between 2003 and 2006, and after a median follow-up of 14 years. We assessed incidences and changes in volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). We investigated the simultaneous presence of severe progression (upper quartile of percentual change volumes). Associations of cardiovascular risk factors with changes in calcification volumes were assessed using multivariate linear regression models. RESULTS: The difference in AAC was most substantial; the median volume (mm3) increased from of 129 to 916 in men and from 93 to 839 in women. For VBAC, no change in volumes was observed though more than a quarter of participants without baseline VBAC developed VBAC during follow-up. Severe progression was most often observed in only one artery at the same time. Hypertension was most consistently associated with increase in calcifications. Associations of diabetes, hypercholesterolemia, and smoking with changes in calcifications varied across arteries and sex. CONCLUSIONS: We found a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors were associated with increase of calcifications with sex-specific differential effects across arteries. CLINICAL RELEVANCE STATEMENT: There is a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors are associated with increase of calcifications with sex-specific differential effects across arteries; thus, assessing changes in only one artery may thus not provide a good reflection of the systemic development of arteriosclerosis. KEY POINTS: • Assessing change in arterial calcification in only one artery does not reflect the systemic development of arterial calcification. • Cardiovascular risk factors are associated with progression of arterial calcifications. • Progression of arterial calcification is sex and artery-specific.

Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population.

INTRODUCTION: The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by screening for UIAs followed by monitoring and, if needed, preventive neurosurgical or endovascular treatment of identified UIAs. Therefore, we developed a diagnostic model for presence of UIAs in the general population to help identify persons at high risk of having UIAs. METHODS: Between 2005-2015, participants from the population-based Rotterdam Study underwent brain magnetic resonance imaging at 1.5 Tesla, on which presence of incidental UIAs was evaluated. We developed a multivariable logistic regression model using candidate diagnostic markers that were selected based on the literature, including sex, age, hypertension, smoking, hypercholesterolemia, diabetes, alcohol, and their interactions. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: 5835 persons were included (55.0% women, mean age 64.9 ± 10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI] 0.60 - 0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cut-off value of 4%. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95% CI 0.62 - 0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95% CI 0.52 - 0.63) with smoking as the only diagnostic marker. CONCLUSION: Our diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.

Cross-Sectional Validation of a Novel Computed Tomography-Based Carotid Mean Calcium Density Measurement.

Background The purpose of this study was to validate a technique for measuring mean calcium density and to determine associations of cardiovascular risk factors with carotid calcium density. Methods and Results We performed a cross-sectional study in a random sample of 100 stroke-free participants from the population-based Rotterdam Study. The mean calcium density of the combined left and right carotid bifurcations was quantified with a threshold of 130 Hounsfield Units (HU) using a novel density technique. To validate the methodology, carotid calcium volumes acquired using the technique in the current study were compared with measurements computed using dedicated clinical software (semiautomatic technique based on a threshold of ≥130 HU). Next, we investigated the associations of participant demographics, total calcium volume, and known cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking status) with the newly derived mean carotid calcium density measurement using linear regression analyses. Calcium volumes obtained with the 2 methods showed a high agreement (intraclass correlation coefficient=0.99, P<0.001), underlining the validity of the density technique. The total calcium volume was statistically significantly associated with the mean calcium density (cardiovascular risk factors adjusted model (B: 0.48 [95% CI, 0.30-0.66], P<0.001). We also found an association between hypercholesterolemia and mean calcium density (0.46 [0.09-0.83], P=0.017). No other significant associations were found between participant demographics or cardiovascular risk factors and mean carotid calcium density. Conclusions We demonstrated the feasibility of a carotid calcium density measurement technique. The data warrant a subsequent longitudinal study to determine the association between carotid calcium density and the risk of cerebrovascular events.

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis.

BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

Lipoprotein(a) is associated with a larger systemic burden of arterial calcification.

AIMS: Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for cardiovascular disease. However, population-based evidence on the link between Lp(a) and subclinical arteriosclerosis is lacking. We assessed associations of Lp(a) concentrations with arteriosclerosis in multiple arteries. METHODS AND RESULTS: From the population-based Rotterdam study, 2354 participants (mean age: 69.5 years, 52.3% women) underwent non-contrast computed tomography to assess arterial calcification as a hallmark of arteriosclerosis. We quantified the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC), and intracranial carotid artery calcification (ICAC). All participants underwent blood sampling, from which plasma Lp(a) concentrations were derived. The association of plasma Lp(a) levels was assessed with calcification volumes and with severe calcification (upper quartile of calcification volume) using sex-stratified multivariable linear and logistic regression models. Higher Lp(a) levels were associated with larger ln-transformed volumes of CAC [fully adjusted beta 95% confidence interval (CI) per 1 standard deviation (SD) in women: 0.09, 95% CI 0.04-0.14, men: 0.09, 95% CI 0.03-0.14], AAC (women: 0.06, 95% CI 0.01-0.11, men: 0.09, 95% CI 0.03-0.14), ECAC (women: 0.07, 95% CI 0.02-0.13, men: 0.08, 95% CI 0.03-0.14), and ICAC (women: 0.09, 95% CI 0.03-0.14, men: 0.05, 95% CI -0.02 to 0.11]. In the highest Lp(a) percentile, severe ICAC was most prevalent in women [fully adjusted odds ratio (OR) 2.41, 95% CI 1.25-4.63] and severe AAC in men (fully adjusted OR 3.29, 95% CI 1.67-6.49). CONCLUSION: Higher Lp(a) was consistently associated with a larger calcification burden in all major arteries. The findings of this study indicate that Lp(a) is a systemic risk factor for arteriosclerosis and thus potentially an effective target for treatment. Lp(a)-reducing therapies may reduce the burden from arteriosclerotic events throughout the arterial system. TRANSLATIONAL PERSPECTIVE: In 2354 participants from the Rotterdam study, we assessed the link between Lp(a) concentrations and arterial calcifications, as proxy for arteriosclerosis, in major arteries. We found that higher Lp(a) levels were consistently associated with larger volumes of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The findings of our study indicate that Lp(a) is a systemic risk factor for arteriosclerosis, suggesting that the systemic burden of arteriosclerosis throughout the arterial system could be reduced by targeting Lp(a).

Aortic Valve Calcium in Relation to Subclinical Cardiac Dysfunction and Risk of Heart Failure.

BACKGROUND: The link between (mild) aortic valve calcium (AVC) with subclinical cardiac dysfunction and with risk of heart failure (HF) remains unclear. This research aims to determine the association of computed tomography-assessed AVC with echocardiographic measurements of cardiac dysfunction, and with HF in the general population. METHODS: We included 2348 participants of the Rotterdam Study cohort (mean age 68.5 years, 52% women), who had AVC measurement between 2003 and 2006, and without history of HF at baseline. Linear regression models were used to explore relationship between AVC and echocardiographic measures at baseline. Participants were followed until December 2016. Fine and Gray subdistribution hazard models were used to assess the association of AVC with incident HF, accounting for death as a competing risk. RESULTS: The presence of AVC or greater AVC were associated with larger mean left ventricular mass and larger mean left atrial size. In particular, AVC ≥800 showed a strong association (body surface area indexed left ventricular mass, ß coefficient: 22.01; left atrium diameter, ß coefficient: 0.17). During a median of 9.8 years follow-up, 182 incident HF cases were identified. After accounting for death events and adjusting for cardiovascular risk factors, one-unit larger log (AVC+1) was associated with a 10% increase in the subdistribution hazard of HF (subdistribution hazard ratio, 1.10 [95% CI, 1.03-1.18]), but the presence of AVC was not significantly associated with HF risk in fully adjusted models. Compared with the AVC=0, AVC between 300 and 799 (subdistribution hazard ratio, 2.36 [95% CI, 1.32-4.19]) and AVC ≥800 (subdistribution hazard ratio, 2.54 [95% CI, 1.31-4.90]) were associated with a high risk of HF. CONCLUSIONS: Presence and high levels of AVC were associated with markers of left ventricular structure, independent of traditional cardiovascular risk factors. Larger computed tomography-assessed AVC is an indicative of increased risk for the development of HF.

Sex Differences in Carotid Atherosclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Over the last decades, several individual studies on sex differences in carotid atherosclerosis have been performed covering a wide range of plaque characteristics and including different populations. This systematic review and meta-analysis aims to summarize previously reported results on sex differences in carotid atherosclerosis and present a roadmap explaining next steps needed for implementing this knowledge in clinical practice. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane Central, and Google Scholar for eligible studies including both male and female participants reporting prevalence of imaging characteristics of carotid atherosclerosis and meta-analyzed these studies. Studies had to report at least the following: (1) calcifications; (2) lipid-rich necrotic core; (3) intraplaque hemorrhage; (4) thin-or-ruptured fibrous cap; (5) plaque ulceration; (6) degree of stenosis; (7) plaque size; or (8) plaque inflammation. We prespecified which imaging modalities had to be used per plaque characteristic and excluded ultrasonography. RESULTS: We included 42 articles in our meta-analyses (ranging from 2 through 23 articles per plaque characteristic). Men had more frequently a larger plaque compared to women and, moreover, had more often plaques with calcifications (odds ratio=1.57 [95% CI, 1.23-2.02]), lipid-rich necrotic core (odds ratio=1.87 [95% CI, 1.36-2.57]), and intraplaque hemorrhage (odds ratio=2.52 [95% CI, 1.74-3.66]), or an ulcerated plaque (1.81 [95% CI, 1.30-2.51]). Furthermore, we found more pronounced sex differences for lipid-rich necrotic core in symptomatic opposed to asymptomatic participants. CONCLUSIONS: In this systematic review and meta-analysis, we demonstrate convincing evidence for sex differences in carotid atherosclerosis. All kinds of plaque features-plaque size, composition, and morphology-were more common or larger in men compared to women. Our results highlight that sex is an important variable to include in both study design and clinical-decision making. Further investigation of sex-specific stroke risks with regard to plaque composition is warranted.

Intracranial Carotid Arteriosclerosis Mediates the Association Between Blood Pressure and Cerebral Small Vessel Disease.

BACKGROUND: Intracranial arteriosclerosis could explain the association between blood pressure (BP) and cerebral small vessel disease (CSVD). Therefore, we tested whether intracranial carotid artery calcification (ICAC) mediates the association between BP and CSVD and determined pathophysiological mechanisms based on ICAC subtypes. METHODS: One thousand four hundred fifty-eight stroke-free participants from the Rotterdam Study (mean age, 68 years; 52% women) underwent nonenhanced computed tomography scans to quantify ICAC volume (mm3) between 2003 and 2015. ICAC was categorized into intimal and internal elastic lamina calcifications. CSVD included white matter hyperintensities volume, the presence of lacunes, and cerebral microbleeds visualized on magnetic resonance imaging. Office BP included systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Mediation analysis included a 2-way decomposition to determine the direct association between BP and CSVD and the indirect or mediated effect (negative or positive mediations expressed in %) of log-ICAC volume on such association. RESULTS: BP and log-ICAC were correlated and were also associated with CSVD. In all participants, total log-ICAC volume mediated the association of diastolic BP (-14.5%) and pulse pressure (16.5%) with log-white matter hyperintensities. Internal elastic lamina log-ICAC volume mediated -19.5% of the association between diastolic BP and log-white matter hyperintensities; intimal log-ICAC volume did not mediate associations. For lacunes, total and internal elastic lamina log-ICAC volume mediated the association of diastolic BP (-40% and -45.8%) and pulse pressure (26.9% and 18.2%). We did not observe mediations for cerebral microbleeds. CONCLUSIONS: Intracranial arteriosclerosis mediates the association between BP and CSVD. Internal elastic lamina calcification, considered a proxy of arterial stiffness, is the leading mechanism explaining the link between BP and CSVD.

Plasma MicroRNA Signature of Alcohol Consumption: The Rotterdam Study.

BACKGROUND: MicroRNAs (miRNAs) represent a class of noncoding RNAs that regulate gene expression and are implicated in the pathogenesis of different diseases. Alcohol consumption might affect the expression of miRNAs, which in turn could play a role in risk of diseases. OBJECTIVES: We investigated whether plasma concentrations of miRNAs are altered by alcohol consumption. Given the existing evidence showing the link between alcohol and liver diseases, we further explored the extent to which these associations are mediated by miRNAs. METHODS: Profiling of plasma miRNAs was conducted using the HTG EdgeSeq miRNA Whole Transcriptome Assay in 1933 participants of the Rotterdam Study. Linear regression was implemented to explore the link between alcohol consumption (glasses/d) and miRNA concentrations, adjusted for age, sex, cohort, BMI, and smoking. Sensitivity analysis for alcohol categories (nondrinkers, light drinkers, and heavy drinkers) was performed, where light drinkers corresponded to 0-2 glasses/d in men and 0-1 glasses/d in women, and heavy drinkers to >2 glasses/d in men and >1 glass/d in women. Moreover, we utilized the alcohol-associated miRNAs to explore their potential mediatory role between alcohol consumption and liver-related traits. Finally, we retrieved putative target genes of identified miRNAs to gain an understanding of the molecular pathways concerning alcohol consumption. RESULTS: Plasma concentrations of miR-193b-3p, miR-122-5p, miR-3937, and miR-4507 were significantly associated with alcohol consumption surpassing the Bonferroni-corrected P < 8.46 × 10-5. The top significant association was observed for miR-193b-3p (ß = 0.087, P = 2.90 × 10-5). Furthermore, a potential mediatory role of miR-3937 and miR-122-5p was observed between alcohol consumption and liver traits. Pathway analysis of putative target genes revealed involvement in biological regulation and cellular processes. CONCLUSIONS: This study indicates that alcohol consumption is associated with plasma concentrations of 4 miRNAs. We outline a potential mediatory role of 2 alcohol-associated miRNAs (miR-3937 and miR-122-5p), laying the groundwork for further exploration of miRNAs as potential mediators between lifestyle factors and disease development.

Volume de Gordura Epicárdica está Associada com Disfunção Endotelial, mas Não com Calcificação Coronariana: Do ELSA-Brasil / Epicardial Fat Volume Is Associated with Endothelial Dysfunction, but not with Coronary Calcification: From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Resumo Fundamento O aumento no volume de gordura epicárdica (VGE) está relacionado com doença arterial coronariana (DAC), independentemente de gordura visceral ou subcutânea. O mecanismo dessa associação não é claro. O escore de cálcio coronariano (CC) e a disfunção endotelial estão relacionados com eventos coronarianos, mas não está bem esclarecido se o VGE está relacionado com esses marcadores. Objetivos Avaliar a associação entre VGE medido por método automatizado, fatores de risco cardiovasculares, escore de CC, e função endotelial. Métodos: Em 470 participantes do Estudo Longitudinal de Saúde do Adulto LSA-Brasil com medidas de VGE, escore de CC e função endotelial, realizamos modelos multivariados para avaliar a relação entre fatore de risco cardiovascular e VGE (variável resposta), e entre VGE (variável explicativa), e função endotelial ou escore de CC. Valor de p<0,05 bilateral foi considerado estatisticamente significativo. Resultados A idade média foi 55 ± 8 anos, e 52,3% dos pacientes eram homens. O VGE médio foi 111mL (86-144), e a prevalência de escore de CC igual a zero foi 55%. Nas análises multivariadas, um VGE mais alto relacionou-se com sexo feminino, idade mais avançada, circunferência da cintura, e triglicerídeos (p<0,001 para todos). Um VGE mais alto foi associado com pior função endotelial: em comparação ao primeiro quartil, os valores de odds ratio para a amplitude de pulso basal foram (q2=1,22; IC95% 1,07-1,40; q3=1,50, IC95% 1,30-1,74; q4=1,50, IC95% 1,28-1,79) e para a razão de tonometria arterial periférica foram (q2=0,87; IC95% 0,81-0,95; q3=0,86, IC95% 0,79-0,94; q4=0,80, IC95% 0,73-0,89), mas não com escore de CC maior que zero. Conclusão Um VGE mais alto associou-se com comprometimento da função endotelial, mas não com escore de CC. Os resultados sugerem que o VGE esteja relacionado ao desenvolvimento de DAC por uma via diferente da via do CC, possivelmente pela piora da disfunção endotelial e doença microvascular.

Abstract Background The increase in epicardial fat volume (EFV) is related to coronary artery disease (CAD), independent of visceral or subcutaneous fat. The mechanism underlying this association is unclear. Coronary artery calcium (CAC) score and endothelial dysfunction are related to coronary events, but whether EFV is related to these markers needs further clarification. Objectives To evaluate the association between automatically measured EFV, cardiovascular risk factors, CAC, and endothelial function. Methods In 470 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) with measures of EFV, CAC score and endothelial function, we performed multivariable models to evaluate the relation between cardiovascular risk factors and EFV (response variable), and between EFV (explanatory variable) and endothelial function variables or CAC score. Two-sided p <0.05 was considered statistically significant. Results Mean age was 55 ± 8 years, 52.3% of patients were men. Mean EFV was 111mL (IQ 86-144), and the prevalence of CAC score=0 was 55%. In the multivariable analyses, increased EFV was related to female sex, older age, waist circumference, and triglycerides (p<0.001 for all). Higher EFV was associated with worse endothelial function: as compared with the first quartile, the odds ratio for basal pulse amplitude were (q2=1.22, 95%CI 1.07-1.40; q3=1.50, 95%CI 1.30-1.74; q4=1.50, 95%CI 1.28-1.79) and for peripheral arterial tonometry ratio were (q2=0.87, 95%CI 0.81-0.95; q3=0.86, 95%CI 0.79-0.94; q4=0.80, 95%CI 0.73-0.89), but not with CAC score>0. Conclusion Higher EFV was associated with impaired endothelial function, but not with CAC. The results suggest that EFV is related to the development of CAD through a pathway different from the CAC pathway, possibly through aggravation of endothelial dysfunction and microvascular disease.

Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA: The PARISK (Plaque At RISK) Study.

BACKGROUND: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making. OBJECTIVES: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. METHODS: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTS: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78). CONCLUSIONS: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025).

Epicardial Fat Volume Is Associated with Endothelial Dysfunction, but not with Coronary Calcification: From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). / Volume de Gordura Epicárdica está Associada com Disfunção Endotelial, mas Não com Calcificação Coronariana: Do ELSA-Brasil.

BACKGROUND: The increase in epicardial fat volume (EFV) is related to coronary artery disease (CAD), independent of visceral or subcutaneous fat. The mechanism underlying this association is unclear. Coronary artery calcium (CAC) score and endothelial dysfunction are related to coronary events, but whether EFV is related to these markers needs further clarification. OBJECTIVES: To evaluate the association between automatically measured EFV, cardiovascular risk factors, CAC, and endothelial function. METHODS: In 470 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) with measures of EFV, CAC score and endothelial function, we performed multivariable models to evaluate the relation between cardiovascular risk factors and EFV (response variable), and between EFV (explanatory variable) and endothelial function variables or CAC score. Two-sided p <0.05 was considered statistically significant. RESULTS: Mean age was 55 ± 8 years, 52.3% of patients were men. Mean EFV was 111mL (IQ 86-144), and the prevalence of CAC score=0 was 55%. In the multivariable analyses, increased EFV was related to female sex, older age, waist circumference, and triglycerides (p<0.001 for all). Higher EFV was associated with worse endothelial function: as compared with the first quartile, the odds ratio for basal pulse amplitude were (q2=1.22, 95%CI 1.07-1.40; q3=1.50, 95%CI 1.30-1.74; q4=1.50, 95%CI 1.28-1.79) and for peripheral arterial tonometry ratio were (q2=0.87, 95%CI 0.81-0.95; q3=0.86, 95%CI 0.79-0.94; q4=0.80, 95%CI 0.73-0.89), but not with CAC score>0. CONCLUSION: Higher EFV was associated with impaired endothelial function, but not with CAC. The results suggest that EFV is related to the development of CAD through a pathway different from the CAC pathway, possibly through aggravation of endothelial dysfunction and microvascular disease.

FUNDAMENTO: O aumento no volume de gordura epicárdica (VGE) está relacionado com doença arterial coronariana (DAC), independentemente de gordura visceral ou subcutânea. O mecanismo dessa associação não é claro. O escore de cálcio coronariano (CC) e a disfunção endotelial estão relacionados com eventos coronarianos, mas não está bem esclarecido se o VGE está relacionado com esses marcadores. OBJETIVOS: Avaliar a associação entre VGE medido por método automatizado, fatores de risco cardiovasculares, escore de CC, e função endotelial. Métodos: Em 470 participantes do Estudo Longitudinal de Saúde do Adulto LSA-Brasil com medidas de VGE, escore de CC e função endotelial, realizamos modelos multivariados para avaliar a relação entre fatore de risco cardiovascular e VGE (variável resposta), e entre VGE (variável explicativa), e função endotelial ou escore de CC. Valor de p<0,05 bilateral foi considerado estatisticamente significativo. RESULTADOS: A idade média foi 55 ± 8 anos, e 52,3% dos pacientes eram homens. O VGE médio foi 111mL (86-144), e a prevalência de escore de CC igual a zero foi 55%. Nas análises multivariadas, um VGE mais alto relacionou-se com sexo feminino, idade mais avançada, circunferência da cintura, e triglicerídeos (p<0,001 para todos). Um VGE mais alto foi associado com pior função endotelial: em comparação ao primeiro quartil, os valores de odds ratio para a amplitude de pulso basal foram (q2=1,22; IC95% 1,07-1,40; q3=1,50, IC95% 1,30-1,74; q4=1,50, IC95% 1,28-1,79) e para a razão de tonometria arterial periférica foram (q2=0,87; IC95% 0,81-0,95; q3=0,86, IC95% 0,79-0,94; q4=0,80, IC95% 0,73-0,89), mas não com escore de CC maior que zero. CONCLUSÃO: Um VGE mais alto associou-se com comprometimento da função endotelial, mas não com escore de CC. Os resultados sugerem que o VGE esteja relacionado ao desenvolvimento de DAC por uma via diferente da via do CC, possivelmente pela piora da disfunção endotelial e doença microvascular.

Potential of a Non-Contrast-Enhanced Abbreviated MRI Screening Protocol (NC-AMRI) in High-Risk Patients under Surveillance for HCC.

PURPOSE: To evaluate NC-AMRI for the detection of HCC in high-risk patients. METHODS: Patients who underwent yearly contrast-enhanced MRI (i.e., full MRI protocol) of the liver were included retrospectively. For all patients, the sequences that constitute the NC-AMRI protocol, namely diffusion-weighted imaging (DWI), T2-weighted (T2W) imaging with fat saturation, and T1-weighted (T1W) in-phase and opposed-phase imaging, were extracted, anonymized, and uploaded to a separate research server and reviewed independently by three radiologists with different levels of experience. Reader I and III held a mutual training session. Levels of suspicion of HCC per patient were compared and the sensitivity, specificity, and area under the curve (AUC) using the Mann-Whitney U test were calculated. The reference standard was a final diagnosis based on full liver MRI and clinical follow-up information. RESULTS: Two-hundred-and-fifteen patients were included, 36 (16.7%) had HCC and 179 (83.3%) did not. The level of agreement between readers was reasonable to good and concordant with the level of expertise and participation in a mutual training session. Receiver operating characteristics (ROC) analysis showed relatively high AUC values (range 0.89-0.94). Double reading showed increased sensitivity of 97.2% and specificity of 87.2% compared with individual results (sensitivity 80.1%-91.7%-97.2%; specificity 91.1%-72.1%-82.1%). Only one HCC (2.8%) was missed by all readers. CONCLUSION: NC-AMRI presents a good potential surveillance imaging tool for the detection of HCC in high-risk patients. The best results are achieved with two observers after a mutual training session.

Genetic Evidence for a Causal Role of Serum Phosphate in Coronary Artery Calcification: The Rotterdam Study.

Background Hyperphosphatemia has been associated with coronary artery calcification (CAC) mostly in chronic kidney disease, but the association between phosphate levels within the normal phosphate range and CAC is unclear. Our objectives were to evaluate associations between phosphate levels and CAC among men and women from the general population and assess causality through Mendelian randomization. Methods and Results CAC, measured by electron-beam computed tomography, and serum phosphate levels were assessed in 1889 individuals from the RS (Rotterdam Study). Phenotypic associations were tested through linear models adjusted for age, body mass index, blood pressure, smoking, prevalent cardiovascular disease and diabetes, 25-hydroxyvitamin D, total calcium, C-reactive protein, glucose, and total cholesterol : high-density lipoprotein cholesterol ratio. Mendelian randomization was implemented through an allele score including 8 phosphate-related single-nucleotide polymorphisms. In phenotypic analyses, serum phosphate (per 1 SD) was associated with CAC with evidence for sex interaction (Pinteraction=0.003) (men ß, 0.44 [95% CI, 0.30-0.59]; P=3×10-9; n=878; women ß, 0.24 [95% CI, 0.08-0.40]; P=0.003; n=1011). Exclusion of hyperphosphatemia, chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and prevalent cardiovascular disease yielded similar results. In Mendelian randomization analyses, instrumented phosphate was associated with CAC (total population ß, 0.93 [95% CI: 0.07-1.79]; P=0.034; n=1693), even after exclusion of hyperphosphatemia, chronic kidney disease and prevalent cardiovascular disease (total population ß, 1.23 [95% CI, 0.17-2.28]; P=0.023; n=1224). Conclusions Serum phosphate was associated with CAC in the general population with stronger effects in men. Mendelian randomization findings support a causal relation, also for serum phosphate and CAC in subjects without hyperphosphatemia, chronic kidney disease, and cardiovascular disease. Further research into underlying mechanisms of this association and sex differences is needed.

Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification.

AIM: Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. METHODS AND RESULTS: A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9-14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2-37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15-1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02-1.65), but not with AVC progression (ß: -71 AU for each 50 mg/dL higher Lp(a); 95% CI -117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). CONCLUSION: In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.