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.

Lesions hyper- to isointense to surrounding liver in the hepatobiliary phase of gadoxetic acid-enhanced MRI.

OBJECTIVES: Hyper- or isointensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI has high specificity for focal nodular hyperplasia (FNH) but may be present in hepatocellular adenoma and carcinoma (HCA/HCC). This study aimed to identify imaging characteristics differentiating FNH and HCA/HCC. MATERIALS AND METHODS: This multicenter retrospective cohort study included patients with pathology-proven FNH or HCA/HCC, hyper-/isointense in the HBP of gadoxetic acid-enhanced MRI between 2010 and 2020. Diagnostic performance of imaging characteristics for the differentiation between FNH and HCA/HCC were reported. Univariable analyses, multivariable logistic regression analyses, and classification and regression tree (CART) analyses were conducted. Sensitivity analyses evaluated imaging characteristics of B-catenin-activated HCA. RESULTS: In total, 124 patients (mean age 40 years, standard deviation 10 years, 108 female) with 128 hyper-/isointense lesions were included. Pathology diagnoses were FNH and HCA/HCC in 64 lesions (50%) and HCA/HCC in 64 lesions (50%). Imaging characteristics observed exclusively in HCA/HCC were raster and atoll fingerprint patterns in the HBP, sinusoidal dilatation on T2-w, hemosiderin, T1-w in-phase hyperintensity, venous washout, and nodule-in-nodule partification in the HBP and T2-w. Multivariable logistic regression and CART additionally found a T2-w scar indicating FNH, less than 50% fat, and a spherical contour indicating HCA/HCC. In our selected cohort, 14/48 (29%) of HCA were B-catenin activated, most (13/14) showed extensive hyper-/isointensity, and some had a T2-w scar (4/14, 29%). CONCLUSION: If the aforementioned characteristics typical for HCA/HCC are encountered in lesions extensively hyper- to isointense, further investigation may be warranted to exclude B-catenin-activated HCA. CLINICAL RELEVANCE: Hyper- or isointensity in the HBP of gadoxetic acid-enhanced MRI is specific for FNH, but HCA/HCC can also exhibit this feature. Therefore, we described imaging patterns to differentiate these entities. KEY POINTS: FNH and HCA/HCC have similar HBP intensities but have different malignant potentials. Six imaging patterns exclusive to HCA/HCC were identified in this lesion population. These features in liver lesions hyper- to isointense in the HBP warrant further evaluation.

Signal intensity and volume of carotid intraplaque hemorrhage on MRI and the risk of ipsilateral cerebrovascular events: the Plaque At RISK (PARISK) study.

BACKGROUND: The Plaque at RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH. METHODS: TIA and ischemic stroke patients with mild-to-moderate carotid stenosis and an ipsilateral IPH-positive carotid plaque (n=89) from the PARISK study were included. The clinical endpoint was a new ipsilateral ischemic cerebrovascular event during 5 years of follow-up, while the imaging-based endpoint was a new ipsilateral brain infarct on brain MRI after 2 years (n=69). Trained observers delineated IPH, a hyperintense region compared to surrounding muscle tissue on hyper T1-weighted MR images. The IPH SIR was the maximal signal intensity in the IPH region divided by the mean signal intensity of adjacent muscle tissue. The associations between IPH SIR or volume and the clinical and imaging-based endpoint were investigated using Cox-proportional hazard models and logistic regression, respectively. RESULTS: During 5.1 (interquartile range (IQR): 3.1-5.6) years of follow-up, 21 ipsilateral cerebrovascular ischemic events were identified. Twelve new ipsilateral brain infarcts were identified on the 2-year neuro MRI. There was no association for IPH SIR or IPH volume with the clinical endpoint (HR: 0.89 [95% CI: 0.67-1.10] and HR: 0.91 [0.69-1.19] per 100µl increase, respectively) nor with the imaging-based endpoint (OR: 1.04 [0.75-1.45] and OR: 1.21 [0.87-1.68] per 100µl increase, respectively). CONCLUSIONS: IPH SIR and IPH volume were not associated with future ipsilateral ischemic cerebrovascular events. Therefore, quantitative assessment of IPH does not seem to provide additional value beyond the presence of IPH for stroke risk assessment. Trial registration The PARISK study was registered on ClinicalTrials.gov with ID NCT01208025 on 21 September 2010 (https://clinicaltrials.gov/study/NCT01208025).

Intracranial arteriosclerosis and the risk of dementia: A population-based cohort study.

BACKGROUND: The impact of intracranial arteriosclerosis on dementia remains largely unclear. METHODS: In 2339 stroke-free and dementia-free participants (52.2% women, mean age 69.5 years) from the general population, we assessed intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC) as proxy for arteriosclerosis. Associations with dementia were assessed using Cox models. In addition, indirect effects through cerebral small vessel disease (cSVD) and subcortical brain structure volumes were assessed using causal mediation analyses. RESULTS: During a median of 13.4 years (25th-75th percentiles 9.9-14.5) of follow-up, 282 participants developed dementia. Both ICAC presence (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.00-2.32]) and volume (HR per standard deviation: 1.19, 95% CI: 1.01-1.40) increased dementia risk. For VBAC, severe calcifications increased dementia risk (HR for third vs first volume tertile: 1.89, 95% CI: 1.00-3.59). These effects were mediated partly through increased cSVD (percentage mediated for ICAC: 13% and VBAC: 24%). DISCUSSION: Intracranial arteriosclerosis increases the risk of dementia.

Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Pathology-based brain arterial disease phenotypes and their radiographic correlates.

INTRODUCTION: Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These diseases not only increase the risk of stroke but also play a significant role in neurodegeneration and dementia. Clear and unambiguous terminology and classification of brain arterial disease phenotypes is crucial for research and clinical practice. MATERIAL AND METHODS: This review aims to summarize and harmonize the terminology used for brain large and small arterial phenotypes based on pathology studies and relate them to imaging phenotypes used in medical research and clinical practice. CONCLUSIONS AND RESULTS: Arteriosclerosis refers to hardening of the arteries but does not specify the underlying etiology. Specific terms such as atherosclerosis, calcification, or non-atherosclerotic fibroplasia are preferred. Atherosclerosis is defined pathologically by an atheroma. Other brain arterial pathologies occur and should be distinguished from atherosclerosis given therapeutic implications. On brain imaging, intracranial arterial luminal stenosis is usually attributed to atherosclerosis in the presence of atherosclerotic risk factors but advanced high-resolution arterial wall imaging has the potential to more accurately identify the underlying pathology. Regarding small vessel disease, arteriosclerosis is ambiguous and arteriolosclerosis is often used to denote the involvement of arterioles rather than arteries. Lipohyalinosis is sometimes used synonymously with arteriolosclerosis, but less accurately describes this common small vessel thickening which uncommonly shows lipid. Specific measures of small vessel wall thickness, the relationship to the lumen as well as changes in the layer composition might convey objective, measurable data regarding the status of brain small vessels.

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.

Advanced glycation end products measured by skin autofluorescence and subclinical cardiovascular disease: the Rotterdam Study.

BACKGROUND: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. METHODS: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. RESULTS: 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. CONCLUSIONS: Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. TRIAL REGISTRATION: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl ) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/ ) under shared catalogue number NTR6831.

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.

Statin Use and Coronary Artery Calcification: a Systematic Review and Meta-analysis of Observational Studies and Randomized Controlled Trials.

PURPOSE OF REVIEW: This review aimed to determine the association between statin use and coronary artery calcification (CAC), as detected by computed tomography in the general population, in previously published observational studies (OSs) and randomized controlled trials (RCTs). RECENT FINDINGS: A systematic search until February 2022 identified 41 relevant studies, comprising 29 OSs and 12 RCTs. We employed six meta-analysis models, stratifying studies based on design and effect metrics. For cohort studies, the pooled ß of the association with CAC quantified by the Agatston score was 0.11 (95% CI = 0.05; 0.16), with an average follow-up time per person (AFTP) of 3.68 years. Cross-sectional studies indicated a pooled odds ratio of 2.11 (95% CI = 1.61; 2.78) for the presence of CAC. In RCTs, the pooled standardized mean differences (SMDs) for CAC, quantified by Agatston score or volume, over and AFTP of 1.25 years were not statistically significant (SMD = - 0.06, 95% CI = - 0.19; 0.06 and SMD = 0.26, 95% CI = - 0.66; 1.19), but significantly different (p-value = 0.04). Meta-regression and subgroup analyses did not show any significant differences in pooled estimates across covariates. The effect of statins on CAC differs across study designs. OSs demonstrate associations between statin use and higher CAC scores and presence while being prone to confounding by indication. Effects from RCTs do not reach statistical significance and vary depending on the quantification method, hampering drawing conclusions. Further investigations are required to address the limitations inherent in each approach.

Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study.

BACKGROUND: It has been suggested that patients with migraine have a higher risk of stroke. Despite considerable research on this topic in younger populations, a clear answer is still lacking for older individuals. We studied the association between migraine and the risk of stroke in a middle-aged and elderly population. METHODS: Within the ongoing prospective population-based Rotterdam Study, the presence of migraine was assessed using a validated questionnaire in a structured interview between 2006 and 2011, which formed the baseline. The association between migraine and the risk of stroke was analyzed using Cox proportional-hazards models with adjustments for age, sex, and cardiometabolic risk factors. RESULTS: A total of 6925 (mean age 65.7 ± 11.3 years, 57.8% females) stroke-free participants were included. At baseline, 1030 (14.9%) participants had lifetime history of migraine. During a median follow-up of 6.2 years, 195 participants developed a stroke (163 ischemic stroke). Analyzing the association between migraine and stroke, we found a hazard ratio of 1.44 with a 95% confidence interval of 0.96-2.15. The results were similar for the ischemic stroke (HR 1.50, CI: 0.97-2.32). CONCLUSION: Our data suggested an association between migraine and the risk of stroke in a middle-aged and elderly population, but this was not statistically significant.

Coronary calcium scoring on virtual non-contrast and virtual non-iodine reconstructions compared to true non-contrast images using photon-counting computed tomography.

OBJECTIVES: To compare coronary artery calcification (CAC) scores measured on virtual non-contrast (VNC) and virtual non-iodine (VNI) reconstructions computed from coronary computed tomography angiography (CCTA) using photon-counting computed tomography (PCCT) to true non-contrast (TNC) images. METHODS: We included 88 patients (mean age = 59 years ± 13.5, 69% male) who underwent a TNC coronary calcium scan followed by CCTA on PCCT. VNC images were reconstructed in 87 patients and VNI in 88 patients by virtually removing iodine from the CCTA images. For all reconstructions, CAC scores were determined, and patients were classified into risk categories. The overall agreement of the reconstructions was analyzed by Bland-Altman plots and the level of matching classifications. RESULTS: The median CAC score on TNC was 27.8 [0-360.4] compared to 8.5 [0.2-101.6] (p < 0.001) on VNC and 72.2 [1.3-398.8] (p < 0.001) on VNI. Bland-Altman plots depicted a bias of 148.8 (ICC = 0.82, p < 0.001) and - 57.7 (ICC = 0.95, p < 0.001) for VNC and VNI, respectively. Of all patients with CACTNC = 0, VNC reconstructions scored 63% of the patients correctly, while VNI scored 54% correctly. Of the patients with CACTNC > 0, VNC and VNI reconstructions detected the presence of coronary calcium in 90% and 92% of the patients. CACVNC tended to underestimate CAC score, whereas CACVNI overestimated, especially in the lower risk categories. According to the risk categories, VNC misclassified 55% of the patients, while VNI misclassified only 32%. CONCLUSION: Compared to TNC images, VNC underestimated and VNI overestimated the actual CAC scores. VNI reconstructions quantify and classify coronary calcification scores more accurately than VNC reconstructions. CLINICAL RELEVANCE STATEMENT: Photon-counting CT enables spectral imaging, which might obviate the need for non-contrast enhanced coronary calcium scoring, but optimization is necessary for the clinical implementation of the algorithms. KEY POINTS: • Photon-counting computed tomography uses spectral information to virtually remove the signal of contrast agents from contrast-enhanced scans. • Virtual non-contrast reconstructions tend to underestimate coronary artery calcium scores compared to true non-contrast images, while virtual non-iodine reconstructions tend to overestimate the calcium scores. • Virtual non-iodine reconstructions might obviate the need for non-contrast enhanced calcium scoring, but optimization is necessary for the clinical implementation of the algorithms.

Epicardial fat volume is related to the degree of cardiac allograft vasculopathy.

OBJECTIVES: Increasing evidence suggests a role for epicardial fat in the development of coronary artery disease in the general population. Heart transplantation patients are at increased risk of developing a specific form of coronary artery disease, cardiac allograft vasculopathy (CAV), which has far-reaching consequences in terms of morbidity and mortality. Until now, the role of epicardial fat volume (EFV) in the development of CAV remains unknown. Hence, we investigated the relationship between EFV and CAV as well as the influence of donor/recipient sex on EFV. METHODS: Adult heart transplant patients who underwent coronary computed tomography angiography (CCTA) for CAV screening who were four or more years post-HT were included. Using the CT examinations, we quantified the EFV and the degree of CAV. Ordinal and linear regression models were used to assess the association of EFV with CAV. RESULTS: In total, 149 (median age 44.5 years, 36% women) patients were included. The median time between HT and the CT scan was 11.0 (7.3-16.1) years. CAV grade 0, 1, 2 and 3 were seen in 85 (57%), 32 (22%), 14 (9%), and 18 (12%) patients, respectively. The median EFV was 208.4 (128.9-276.0) mL. Larger EFV were related to higher degrees of CAV (median of 164.7 to 290.6 mL for CAV grade 0 and 3, respectively, OR 5.23 (2.47-11.06), p < 0.001). Male recipients had significantly more EFV than female recipients irrespective of the donor sex (232.7 mL vs. 147.2 mL respectively, p < 0.001). Determinants for EFV were recipient sex, number of rejections, donor age, time between HT and CT scan, recipient BMI, and diabetes mellitus. CONCLUSIONS: EFV was associated with higher degrees of CAV. The recipient sex influenced the EFV more than the donor sex. KEY POINTS: • Patients after heart transplantation have a high amount of epicardial fat while larger amounts of epicardial fat are related to higher grades of cardiac allograft vasculopathy. • Determinants of higher epicardial fat volume included recipient sex, number of rejections, donor age, time between HT and CT scan, recipient BMI, and diabetes mellitus. • Longitudinal studies are needed to further disentangle the role of epicardial fat in the development and progression of cardiac allograft vasculopathy. Demonstration of four patients (from CAV grade 0 to CAV grade 3) in whom epicardial fat volume was determined. In red, the voxels identified as epicardial fat.

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.

The association between antiplatelet therapy and changes in intraplaque hemorrhage in patients with mild to moderate symptomatic carotid stenosis: a longitudinal MRI study.

INTRODUCTION: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated changes in IPH over two years in patients who recently started versus those with continued antiplatelet use. METHODS: In the Plaque at Risk (PARISK) study, symptomatic patients with <70% ipsilateral carotid stenosis underwent carotid plaque MRI at baseline and after two years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. IPH volume change over a period of two years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and 1) newly developed ipsilateral or contralateral IPH and 2) IPH volume progression. RESULTS: A total of 108 patients underwent carotid MRI at baseline and follow-up. At baseline, previous antiplatelet therapy was associated with any IPH (OR=5.6, 95% CI: 1.3-23.1; p=0.02). Ipsilateral IPH volume did not change significantly during the two years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2-235.9] vs. 59.3 mm3 [11.4-260.3]; p=0.6) nor in the new antiplatelet users (n=31) (61.5 mm3 [0.0-166.9] vs. 27.7 mm3 [9.5-106.4]; p=0.4). Similar results of a nonsignificant change in contralateral IPH volume during those two years were observed in both groups (p>0.05). No significant associations were found between new antiplatelet use and newly developed IPH at two years (odds ratio (OR)=1.0, 95% CI:0.1-7.4) or the progression of IPH (ipsilateral: OR=2.4, 95% CI:0.3-19.1; contralateral: OR=0.3, 95% CI:0.01-8.5). CONCLUSION: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after TIA/stroke was not associated with newly developed IPH or progression of IPH volume over the subsequent two years.

No association between blood-based markers of immune system and migraine status: a population-based cohort study.

BACKGROUND: Although some evidence implicates the immune system in migraine attacks, its role during attack-free periods remains largely unexplored. Therefore, we assessed the association between the immune system and migraine status. METHODS: From the population-based Rotterdam Study, we included 6593 participants who underwent blood sampling and migraine assessments. In the blood samples, we measured white blood-cell-based immune markers. As a marker for the innate immune system, granulocyte and platelet counts were determined, whereas lymphocyte counts were used as a marker for the adaptive immune system. Migraine was assessed using a validated questionnaire based on ICHD-2 criteria. We investigated associations between blood-cell counts and migraine using logistic regression models adjusting for age, sex and other variables. RESULTS: Mean age of participants was 65.6 ± 11.2 years and 56.7% were female. The lifetime prevalence of migraine was 15.1% (995/6593). We found no statistically significant associations between granulocyte (odds ratio [OR] per standard deviation increase 1.01 95% Confidence Interval [CI]: 0.93-1.09), platelet (OR 1.01 CI: 0.94-1.09) or lymphocyte counts (OR 1.01 CI: 0.93-1.08) and migraine status. CONCLUSIONS: Our results do not support an association between white blood-cell-based immunity markers and migraine status.

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.

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.

Importance: Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. Objective: To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Design, Setting, and Participants: Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Exposure: Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Main Outcomes and Measures: Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. Results: The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). Conclusions and Relevance: In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.

The role of intracranial artery calcification (IAC) in stroke subtype and risk of vascular events.

OBJECTIVE: To test the hypothesis that intracranial arterial calcification (IAC) is associated with intracranial large artery stenosis (ILAS) and a higher risk of vascular events and mortality. METHOD: We leveraged data from two cohorts, the New York-Presbyterian Hospital/Columbia University Irving Medical Center Stroke Registry Study (NYP/CUIMC-SRS) and the Northern Manhattan Study (NOMAS) to test our hypotheses. We measured IAC using CT scans of participants in both cohorts and expressed IAC as present (vs not) and in tertiles. For the CUIMC-SRS, demographic, clinical and ILAS status was collected retrospectively. In NOMAS, we used research brain MRI and MRA to define asymptomatic ILAS and covert brain infarcts(CBI). We built models adjusted for demographics and vascular risk factors for cross-sectional and longitudinal analyses. RESULTS: Cross-sectionally, IAC was associated with ILAS in both cohorts (OR 1.78, 95% CI: 1.16-2.73 for ILAS-related stroke in the NYP/CUIMC-SRS and OR 3.07, 95%CI 1.13-8.35 for ILAS-related covert brain infarcts in NOMAS). In a meta-analysis of both cohorts, IAC in the upper (HR 1.25, 95%CI 1.01-1.55) and middle tertile (HR 1.27, 95%CI 1.01-1.59) was associated with higher mortality compared with participants with no IAC. There were no longitudinal associations between IAC and risk of stroke or other vascular events. CONCLUSION: In these multiethnic populations, IAC is associated with symptomatic and asymptomatic ILAS as well as higher mortality. IAC may be a useful marker of higher mortality, the role of IAC as an imaging marker of risk of stroke is less certain.