Publications by authors named "Maryam Kavousi"

192 Publications

Morphological Subtypes of Intracranial Internal Carotid Artery Arteriosclerosis and the Risk of Stroke.

Stroke 2021 Nov 22:STROKEAHA121036213. Epub 2021 Nov 22.

Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. (T.C.v.d.B., J.E.v.d.T., M.W.V., M.K., M.K.I., D.B.).

Background And Purpose: Accumulating evidence highlights the existence of distinct morphological subtypes of intracranial carotid arteriosclerosis. So far, little is known on the prevalence of these subtypes and subsequent stroke risk in the general population. We determined the prevalence of morphological subtypes of intracranial arteriosclerosis and assessed the risk of stroke associated with these subtypes.

Methods: Between 2003 and 2006, 2391 stroke-free participants (mean age 69.6, 51.7% women) from the population-based Rotterdam Study underwent noncontrast computed tomography to visualize calcification in the intracranial carotid arteries as a proxy for intracranial arteriosclerosis. Calcification morphology was evaluated according to a validated grading scale and categorized into intimal, internal elastic lamina (IEL), or mixed subtype. Follow-up for stroke was complete until January 1, 2016. We used multivariable Cox regression to assess associations of each subtype with incident stroke.

Results: The prevalence of calcification was 82% of which 39% had the intimal subtype, 48% IEL subtype, and 13% a mixed subtype. During a median follow-up of 10.4 years, 155 participants had a stroke. All 3 subtypes were associated with a higher risk of stroke (adjusted hazard ratio [95% CI] for intimal: 2.11 [1.07-4.13], IEL: 2.66 [1.39-5.11], and mixed subtype 2.57 [1.18-5.61]). The association of the IEL subtype with stroke was strongest among older participants. The association of the intimal subtype with stroke was noticeably stronger in women than in men.

Conclusions: Calcification of the IEL was the most prevalent subtype of intracranial arteriosclerosis. All 3 subtypes were associated with an increased risk of stroke, with noticeable age and sex-specific differences.
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http://dx.doi.org/10.1161/STROKEAHA.121.036213DOI Listing
November 2021

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

Diabetes Care 2021 Nov 17. Epub 2021 Nov 17.

Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC.

Objective: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.

Research Design And Methods: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.

Results: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect ( = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% ( = 0.04).

Conclusions: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.
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http://dx.doi.org/10.2337/dc21-1284DOI Listing
November 2021

Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Hum Mol Genet 2021 Nov 12. Epub 2021 Nov 12.

LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent genome-wide association study on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD, and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL, and TLN2 as new candidate genes whose differential expression might modulate cIMT.
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http://dx.doi.org/10.1093/hmg/ddab236DOI Listing
November 2021

Arterial calcification at different sites and prediction of atherosclerotic cardiovascular disease among women and men.

Atherosclerosis 2021 Oct 19;337:27-34. Epub 2021 Oct 19.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Background And Aims: The sex-specific contributions of arterial calcification to atherosclerotic cardiovascular disease (ASCVD) risk prediction and stratification in the light of recent modifications by cardiovascular prevention guidelines remain unclear. We assessed the sex-specific value of calcification in different arteries, beyond the Pooled Cohort Equations (PCE) risk factors, for 10-year ASCVD risk prediction.

Methods: From 2003 to 2006, participants from the population-based Rotterdam Study (n = 2167) underwent CT to quantify coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC). Follow-up for ASCVD was complete on January 1, 2015. We refitted the PCE (base model), and categorized participants into low (<5%), borderline (5%-7.5%), intermediate (7.5%-20%), and high (≥20%) ASCVD risk. We extended the models with calcifications and calculated c-statistics and net reclassification improvements for events (NRI) and non-events (NRI).

Results: CAC predicted ASCVD in women [hazard-ratio (95%-CI) per 1-SD: 1.40 (1.14-1.73)] and men [1.62 (1.27-1.93)]. After addition of CAC to the base model, the c-statistic improved from 0.71 to 0.72 in women; from 0.65 to 0.68 in men. Addition of CAC led to NRI of 14.3% in women, 4.8% in men and NRI of 1.5% in women, 15.1% in men. Only in women, ICAC predicted ASCVD [hazard-ratio (95%-CI) per 1-SD: 1.62 (1.26-2.08)], and improved the model (c-statistic from 0.71 to 0.73, NRI: 9.8% and NRI: 5.9%).

Conclusions: Assessment of CAC improves ASCVD risk prediction and stratification. In women, the added value of ICAC for ASCVD risk prediction is comparable to that of CAC.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.10.009DOI Listing
October 2021

Associations between macronutrient intake and coronary heart disease (CHD): The Rotterdam Study.

Clin Nutr 2021 11 4;40(11):5494-5499. Epub 2021 Sep 4.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Nutrition and Dietetics, Faculty of Health, Nutrition and Sport, The Hague University of Applied Sciences, the Netherlands. Electronic address:

Background & Aims: Dietary intake of several specific macronutrients has been linked to risk of coronary heart disease (CHD). However, these associations may depend on overall macronutrient composition rather than effects of one single macronutrient. Therefore, we aimed to investigate the associations of macronutrient intake and CHD and its related risk factors, by taking into account different macronutrient substitutions.

Methods: This study was performed among 5873 participants from the Rotterdam Study, a population-based cohort study. Macronutrient intake was measured using a semi-quantitative food-frequency questionnaire. Cox proportional hazard regression analyses were used to examine associations between intakes of macronutrients and CHD incidence; and linear regression analyses were used to examine associations with the related risk factors, including triglycerides, total, high-density and low-density cholesterol levels, body mass index (BMI), fat mass index (FMI), and fat-free mass index (FFMI).

Results: We documented 669 CHD cases during 74,776 person-years of follow-up. In multivariable-adjusted models we observed no statistically significant associations between macronutrients and CHD incidence. Although non-significant, a higher plant protein intake tended to be associated with a lower risk of CHD when consumed at the expense of any of the other macronutrients. This association was strongest when 5% of energy (5 E%) of plant protein was consumed at the expense of animal protein (HR = 0.61; 95% CI 0.31, 1,21), mono- and disaccharides (HR = 0.62; 95% CI 0.29, 1.35) or saturated fat (HR = 0.61; 95% CI 0.31, 1.20). No consistent associations were observed for risk factors related to CHD.

Conclusions: Macronutrient composition was not significantly associated with CHD incidence or cardiometabolic risk factors in an adult population. Future studies should further investigate food sources and quality of macronutrients.
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http://dx.doi.org/10.1016/j.clnu.2021.08.022DOI Listing
November 2021

A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin.

Pharmacogenomics J 2021 Oct 6. Epub 2021 Oct 6.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.
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http://dx.doi.org/10.1038/s41397-021-00256-2DOI Listing
October 2021

Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes.

Eur J Prev Cardiol 2021 Sep 28. Epub 2021 Sep 28.

Department of Epidemiology, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Aims: Data on the lifetime risk of type 2 diabetes (T2D) incidence across different cardiovascular health (CVH) categories are scarce. Moreover, it remains unclear whether a genetic predisposition modifies this association.

Methods And Results: Using data from the prospective population-based Rotterdam Study, a CVH score (body mass index, blood pressure, total cholesterol, smoking status, diet, and physical activity) was calculated and further categorized at baseline. Genetic predisposition to T2D was assessed and divided into tertiles by creating a genetic risk score (GRS). We estimated the lifetime risk for T2D within different CVH and GRS categories. Among 5993 individuals free of T2D at baseline [mean (standard deviation) age, 69.1 (8.5) years; 58% female], 869 individuals developed T2D during follow-up. At age 55 years, the remaining lifetime risk of T2D was 22.6% (95% CI: 19.4-25.8) for ideal, 28.3% (25.8-30.8) for intermediate, and 32.6% (29.0-36.2) for poor CVH. After further stratification by GRS tertiles, the lifetime risk for T2D was still the lowest for ideal CVH in the lowest GRS tertiles [21.5% (13.7-29.3)], in the second GRS tertile [20.8% (15.9-25.8)], and in the highest tertile [23.5% (18.5-28.6)] when compared with poor and intermediate CVH.

Conclusion: Our results highlight the importance of favourable CVH in preventing T2D among middle-aged individuals regardless of their genetic predisposition.
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http://dx.doi.org/10.1093/eurjpc/zwab141DOI Listing
September 2021

Immunothrombosis and new-onset atrial fibrillation in the general population: the Rotterdam Study.

Clin Res Cardiol 2021 Sep 24. Epub 2021 Sep 24.

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. The etiology underlying AF is still largely unknown. At the intersection of the innate immune system and hemostasis, immunothrombosis may be a possible cause of atrial remodeling, and therefore be an underlying cause of AF.

Methods: From 1990 to 2014, we followed participants aged 55 and over, free from AF at inclusion. Immunothrombosis factors fibrinogen, von Willebrand factor, ADAMTS13, and neutrophil extracellular traps (NETs) levels were measured at baseline. Participants were followed until either onset of AF, loss-to-follow-up, or reaching the end-date of 01-01-2014. Cox proportional hazard modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for cardiovascular risk factors.

Results: We followed 6174 participants (mean age 69.1 years, 57% women) for a median follow-up time of 12.8 years. 364 men (13.7%, incidence rate 13.0/1000 person-years) and 365 women (10.4%, incidence rate 8.9/1000 person-years) developed AF. We found no significant association between markers of immunothrombosis and new-onset AF after adjusting for cardiovascular risk factors [HR 1.00 (95% CI 0.93-1.08) for fibrinogen, 1.04 (0.97-1.12) for von Willebrand factor, 1.00 (1.00-1.01) for ADAMTS13, and 1.01 (0.94-1.09) for NETs]. In addition, we found no differences in associations between men and women.

Conclusion: We found no associations between markers of immunothrombosis and new-onset AF in the general population. Inflammation and immunothrombosis may be associated with AF through other cardiovascular risk factors or predisposing conditions of AF. Our findings challenge the added value of biomarkers in AF risk prediction.
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http://dx.doi.org/10.1007/s00392-021-01938-4DOI Listing
September 2021

Recommendations and Associated Levels of Evidence for Statin Use in Primary Prevention of Cardiovascular Disease: A Comparison at Population Level of the American Heart Association/American College of Cardiology/Multisociety, US Preventive Services Task Force, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society Clinical Practice Guidelines.

Circ Cardiovasc Qual Outcomes 2021 09 21;14(9):e007183. Epub 2021 Sep 21.

Department of Epidemiology (J.P., M.K., M.K.I., J.W.D., M.A.I., M.J.G.L.), Erasmus MC - University Medical Center Rotterdam, the Netherlands.

Background: Despite using identical evidence to support practice guidelines for lipid-lowering treatment in primary prevention of cardiovascular disease (CVD), it is unclear to what extent the 2018 American Heart Association/American College of Cardiology/Multisociety, 2016 US Preventive Services Task Force (USPSTF), 2020 Department of Veterans Affairs/Department of Defense, 2021 Canadian Cardiovascular Society, and 2019 European Society of Cardiology/European Atherosclerosis Society guidelines differ in grading and assigning levels of evidence and classes of recommendations (LOE/class) at a population level.

Methods: We included 7262 participants, aged 45 to 75 years, without history of CVD from the prospective population-based Rotterdam Study. Per guideline, proportions of the population recommended statin therapy by LOE/class, sensitivity and specificity for CVD events, and numbers needed to treat at 10 years were calculated.

Results: Mean age was 61.1 (SD 6.9) years; 58.2% were women. American Heart Association/American College of Cardiology/Multisociety, USPSTF, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society strongly recommended statin initiation in respective 59.4%, 40.2%, 45.2%, 73.7%, and 42.1% of the eligible population based on high-quality evidence. Sensitivity for CVD events for treatment recommendations supported with strong LOE/class was 86.3% for American Heart Association/American College of Cardiology/Multisociety (IA or IB), 69.4% for USPSTF (USPSTF-B), 74.5% for Department of Veterans Affairs/Department of Defense (strong for), 93.3% for Canadian Cardiovascular Society (strong), and 66.6% for European Society of Cardiology/European Atherosclerosis Society (IA). Specificity was highest for the USPSTF at 45.3% and lowest for European Society of Cardiology/European Atherosclerosis Society at 10.0%. Estimated numbers needed to treat at 10 years for those with the strongest LOE/class were ranging from 20 to 26 for moderate-intensity and 12 to 16 for high-intensity statins.

Conclusions: Sensitivity, specificity, and numbers needed to treat at 10 years for assigned LOE/class varied greatly among 5 CVD prevention guidelines. The level of variability seems to be driven by differences in how the evidence is graded and translated into LOE/class underlying the treatment recommendations by different professional societies. Efforts towards harmonizing evidence grading systems for clinical guidelines in primary prevention of CVD may reduce ambiguity and reinforce updated evidence-based recommendations.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007183DOI Listing
September 2021

Sex-specific normal values and determinants of infrarenal abdominal aortic diameter among non-aneurysmal elderly population.

Sci Rep 2021 09 7;11(1):17762. Epub 2021 Sep 7.

Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

To establish age- and sex-specific distribution of the infrarenal abdominal aortic diameters (IAD) among non-aneurysmal elderly population and to investigate the associations between traditional cardiovascular risk factors and IAD in men and women. We included 4032 participants (mean age 67.2 years; 60.4% women) from the population-based Rotterdam Study, free of cardiovascular disease, who underwent IAD ultrasound assessment between 2009-2014. Linear regression analysis was used to identify determinants of IAD. The medians (inter-quartile range) of absolute IAD and body surface area (BSA)-adjusted IAD were 17.0 (15.0-18.0) mm and 9.3 (8.5-10.2) mm for women and 19.0 (18.0-21.0) mm and 9.4 (8.6-10.3) mm for men, respectively. There was a non-linear relationship between age and IAD. IAD increased steeply with advancing age and up to 70 years. After around 75 years of age, the diameter values reached a plateau. Waist circumference and diastolic blood pressure were associated with larger diameters in both sexes. Body mass index [Effect estimate (95% CI): 0.04 (0.00 to 0.08)], systolic blood pressure [- 0.01(- 0.02 to 0.00)], current smoking [0.35 (0.06 to 0.65)], total cholesterol levels [- 0.21 (- 0.31 to - 0.11)], and lipid-lowering medication [- 0.43 (- 0.67 to - 0.19)] were significantly associated with IAD in women. Sex differences in IAD values diminished after taking BSA into account. The increase in diameters was attenuated after 70 years. Differences were observed in the associations of several cardiovascular risk factors with IAD among men and women.
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http://dx.doi.org/10.1038/s41598-021-97209-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423780PMC
September 2021

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods And Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Impaired fasting glucose, type 2 diabetes mellitus, and lifetime risk of cardiovascular disease among women and men: the Rotterdam Study.

BMJ Open Diabetes Res Care 2021 08;9(1)

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Introduction: Data on sex-specific lifetime risk of cardiovascular disease (CVD) across the glycemic spectrum, in particular in impaired fasting glucose (IFG) state, are scarce. Whether overweight/obesity modifies the CVD burden also remains unclear.

Research Design And Methods: Using a prospective population-based Rotterdam Study, normoglycemia, IFG, and type 2 diabetes mellitus (T2D) were defined. First incident cases of coronary heart disease, heart failure, and stroke during a follow-up time until January 1, 2015 were identified and formed the composite CVD end point. The remaining lifetime risks of CVD were estimated in each glucose category at 55, 65, 75, and 85 years of age, using a modified version of survival analysis adjusted for the competing risk of death.

Results: Among 5698 women and 3803 men free of CVD at baseline, the mean age was 64.5 years (SD 9.6) and 60.0% of participants were women. At age 55 years, the remaining lifetime risk of any CVD event among women was 55.1% (95% CI 48.3 to 61.9) for IFG, compared with 52.7% (95% CI 49.5 to 55.9) for normoglycemia and 61.5% (95% CI 54.7 to 68.3) for T2D. For men, the remaining lifetime risk of any CVD event was 62.1% (95% CI 55.2 to 69.1) for IFG, compared with 59.1% (95% CI 55.5 to 62.7) for normoglycemia and 60.3% (95% CI 53.1 to 67.5) for T2D. At age 55 years, the lifetime risk for incident CVD was higher, although not statistically significant, among women and men with IFG who were overweight or had obesity compared with normal-weight women and men.

Conclusion: IFG carried a large lifetime risk for incident CVD among both women and men compared with normoglycemia. In particular among men, the risk was comparable to that of T2D. Overweight/Obesity modifies the risk and conferred a larger burden of lifetime CVD risk among women and men with IFG.
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http://dx.doi.org/10.1136/bmjdrc-2021-002406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388277PMC
August 2021

Association of Insulin Resistance and Type 2 Diabetes With Gut Microbial Diversity: A Microbiome-Wide Analysis From Population Studies.

JAMA Netw Open 2021 07 1;4(7):e2118811. Epub 2021 Jul 1.

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Importance: Previous studies have indicated that gut microbiome may be associated with development of type 2 diabetes. However, these studies are limited by small sample size and insufficient for confounding. Furthermore, which specific taxa play a role in the development of type 2 diabetes remains unclear.

Objective: To examine associations of gut microbiome composition with insulin resistance and type 2 diabetes in a large population-based setting controlling for various sociodemographic and lifestyle factors.

Design, Setting, And Participants: This cross-sectional analysis included 2166 participants from 2 Dutch population-based prospective cohorts: the Rotterdam Study and the LifeLines-DEEP study.

Exposures: The 16S ribosomal RNA method was used to measure microbiome composition in stool samples collected between January 1, 2012, and December 31, 2013. The α diversity (Shannon, richness, and Inverse Simpson indexes), β diversity (Bray-Curtis dissimilarity matrix), and taxa (from domain to genus level) were identified to reflect gut microbiome composition.

Main Outcomes And Measures: Associations among α diversity, β diversity, and taxa with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and with type 2 diabetes were examined. Glucose and insulin were measured to calculate the HOMA-IR. Type 2 diabetes cases were identified based on glucose levels and medical records from January 2012 to December 2013. Analyses were adjusted for technical covariates, lifestyle, sociodemographic, and medical factors. Data analysis was performed from January 1, 2018, to December 31, 2020.

Results: There were 2166 participants in this study: 1418 from the Rotterdam Study (mean [SD] age, 62.4 [5.9] years; 815 [57.5%] male) and 748 from the LifeLines-DEEP study (mean [SD] age, 44.7 [13.4] years; 431 [57.6%] male); from this total, 193 type 2 diabetes cases were identified. Lower microbiome Shannon index and richness were associated with higher HOMA-IR (eg, Shannon index, -0.06; 95% CI, -0.10 to -0.02), and patients with type 2 diabetes had a lower richness than participants without diabetes (odds ratio [OR], 0.93; 95% CI, 0.88-0.99). The β diversity (Bray-Curtis dissimilarity matrix) was associated with insulin resistance (R2 = 0.004, P = .001 in the Rotterdam Study and R2 = 0.005, P = .002 in the LifeLines-DEEP study). A total of 12 groups of bacteria were associated with HOMA-IR or type 2 diabetes. Specifically, a higher abundance of Christensenellaceae (β = -0.08; 95% CI, -0.12 to -0.03: P < .001), Christensenellaceae R7 group (β = -0.07; 95% CI, -0.12 to -0.03; P < .001), Marvinbryantia (β = -0.07; 95% CI, -0.11 to -0.03; P < .001), Ruminococcaceae UCG005 (β = -0.09; 95% CI, -0.13 to -0.05; P < .001), Ruminococcaceae UCG008 (β = -0.07; 95% CI, -0.11 to -0.03; P < .001), Ruminococcaceae UCG010 (β = -0.08; 95% CI, -0.12 to -0.04; P < .001), or Ruminococcaceae NK4A214 group (β = -0.09; 95% CI, -0.13 to -0.05; P < .001) was associated with lower HOMA-IR. A higher abundance of Clostridiaceae 1 (OR, 0.51; 95% CI, 0.41-0.65; P < .001), Peptostreptococcaceae (OR, 0.56; 95% CI, 0.45-0.70; P < .001), C sensu stricto 1 (OR, 0.51; 95% CI, 0.40-0.65; P < .001), Intestinibacter (OR, 0.60; 95% CI, 0.48-0.76; P < .001), or Romboutsia (OR, 0.55; 95% CI, 0.44-0.70; P < .001) was associated with less type 2 diabetes. These bacteria are all known to produce butyrate.

Conclusions And Relevance: In this cross-sectional study, higher microbiome α diversity, along with more butyrate-producing gut bacteria, was associated with less type 2 diabetes and with lower insulin resistance among individuals without diabetes. These findings could help provide insight into the etiology, pathogenesis, and treatment of type 2 diabetes.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.18811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322996PMC
July 2021

Heart failure and promotion of physical activity before and after cardiac rehabilitation (HF-aPProACH): a study protocol.

ESC Heart Fail 2021 10 16;8(5):3621-3627. Epub 2021 Jul 16.

Department of Cardiology, Thorax Centre, Erasmus MC, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands.

Aims: Lifestyle changes, such as increasing physical activity (PA), are a cornerstone of treatment of patients with chronic heart failure (HF). However, improving PA in HF patients is challenging, and low participation rates for cardiac rehabilitation (CR) as well as relapse to low PA levels after CR are major issues. We designed a randomized controlled trial to investigate if PA monitoring with motivational feedback before and after centre-based CR in HF patients with reduced ejection fraction (HFrEF) will lead to a clinically meaningful increase in physical fitness.

Methods And Results: A randomized controlled trial will be conducted in a sample of 180 HFrEF patients (New York Heart Association Class II/III) who are referred to 12-week standard CR. Patients will be randomized (2:1) to (1) standard of care (SoC) plus wearing a PA monitoring device (Fitbit Charge 3) with personalized step goals, feedback and motivation or (2) SoC only. The intervention lasts ±7 months: 4-5 weeks before CR, 12 weeks during CR and 12 weeks after CR. Measurements will take place at three time points. The primary endpoint is the change in the distance in 6-min walking test (6MWT) over the entire study period. Other endpoints include step count, grip strength, quality of life and all-cause mortality or hospitalization.

Conclusions: HF-aPProACH will provide novel information on the effectiveness of remote PA stimulation and feedback before, during and after standard CR using a commercially available device to improve physical fitness in HFrEF patients.
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http://dx.doi.org/10.1002/ehf2.13505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497333PMC
October 2021

Genetic susceptibility, obesity and lifetime risk of type 2 diabetes: The ARIC study and Rotterdam Study.

Diabet Med 2021 Oct 2;38(10):e14639. Epub 2021 Aug 2.

Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Aims: Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown.

Methods: We used data from 15,671 diabetes-free participants of European ancestry aged 45 years and older from the prospective population-based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk.

Results: At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group.

Conclusions: Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk.
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http://dx.doi.org/10.1111/dme.14639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429251PMC
October 2021

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

Circ Genom Precis Med 2021 08 9;14(4):e003258. Epub 2021 Jul 9.

Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

Results: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435075PMC
August 2021

Aging, Cardiovascular Risk, and SHBG Levels in Men and Women From the General Population.

J Clin Endocrinol Metab 2021 09;106(10):2890-2900

Department of Internal Medicine, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.

Aims: Prior studies have reported inconsistent results for the association between sex hormone-binding globulin (SHBG) and cardiovascular disease among men and women. Although it is suggested that SHBG levels change with aging, the exact trend of SHBG across age and cardiovascular risk and the underlying mechanisms of these changes remain to be elucidated.

Methods: Using data of 3264 men and women from a large population-based cohort study, we first visualized the distribution of serum SHBG levels across age. Second, we computed a cardiovascular risk factor sum score and investigated the mean SHBG levels across categories of the risk factor sum score and stratified per age-category. Next, linear regression models were used to investigate the associations between serum SHBG levels and age and potential regulators of SHBG, including body mass index (BMI), fasting insulin, sex steroids, thyroxine, and triglycerides.

Results: Among men, a linear increase in SHBG levels with age and among women a U-shaped pattern was observed. Participants with larger number of cardiovascular risk factors had lower SHBG levels. When stratified by age, older participants had higher SHBG levels. A multivariate model including total testosterone and triglyceride levels in men and total testosterone, triglycerides, BMI, and fasting insulin in women explained, respectively, 46.2% and 31.8% of the variance in SHBG levels.

Conclusion: We observed a clear sex-specific pattern for SHBG levels with age. Our findings highlight the importance of taking into account the age-related changes in SHBG levels to avoid controversial results in the assessment of the cardiovascular risk associated with SHBG.
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http://dx.doi.org/10.1210/clinem/dgab470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475196PMC
September 2021

C-factor: a summary measure for systemic arterial calcifications.

BMC Cardiovasc Disord 2021 06 29;21(1):317. Epub 2021 Jun 29.

Departments of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

Background: Arterial calcification, the hallmark of arteriosclerosis, has a widespread distribution in the human body with only moderate correlation among sites. Hitherto, a single measure capturing the systemic burden of arterial calcification was lacking. In this paper, we propose the C-factor as an overall measure of calcification burden.

Methods: To quantify calcification in the coronary arteries, aortic arch, extra- and intracranial carotid arteries, and vertebrobasilar arteries, 2384 Rotterdam Study participants underwent cardiac and extra-cardiac non-enhanced CT. We performed principal component analyses on the calcification volumes of all twenty-six possible combinations of these vessel beds. Each analysis' first principal component represents the C-factor. Subsequently, we determined the correlation between the C-factor derived from all vessel beds and the other C-factors with intraclass correlation coefficient (ICC) analyses. Finally, we examined the association of the C-factor and calcification in the separate vessel beds with cardiovascular, non-cardiovascular, and overall mortality using Cox-regression analyses.

Results: The ICCs ranged from 0.80 to 0.99. Larger calcification volumes and a higher C-factor were all individually associated with higher risk of cardiovascular, non-cardiovascular, and overall mortality. When included simultaneously in a model, the C-factor was still associated with all three mortality types (adjusted hazard ratio per standard deviation increase (HR) > 1.52), whereas associations of the separate vessel beds with mortality attenuated substantially (HR < 1.26).

Conclusions: The C-factor summarizes the systemic component of arterial calcification on an individual level and appears robust among different combinations of vessel beds. Importantly, when mutually adjusted, the C-factor retains its strength of association with mortality while the site-specific associations attenuate.
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http://dx.doi.org/10.1186/s12872-021-02126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243490PMC
June 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Nov 6;36(11):1143-1155. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
November 2021

Intracranial arteriosclerosis is related to cerebral small vessel disease: a prospective cohort study.

Neurobiol Aging 2021 09 22;105:16-24. Epub 2021 Apr 22.

Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Intracranial arteriosclerosis has been increasingly recognized as a risk factor for cognitive impairment and even dementia. A possible mechanism linking intracranial arteriosclerosis to cognitive impairment and dementia involves structural brain changes including cerebral small vessel disease (CSVD). To assess whether intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC), as proxies for intracranial arteriosclerosis, are related to CSVD. Within the population-based Rotterdam Study, between 2003 and 2006 a computed tomography (CT)-based measurement of ICAC and VBAC and at least one magnetic resonance imaging (MRI) measurement of structural brain changes were performed from 2005 onwards in 1,489 participants. To estimate the burden of calcification independent of age, we computed age-adjusted percentile curves for ICAC and VBAC separately, based on the calcification volumes. Using the longitudinal MRI data, we assessed whether a larger calcification burden accelerates structural brain changes using appropriate statistical models for repeated outcome measures. A larger burden of ICAC and VBAC was associated with an increase of CSVD markers accelerating over time. A larger burden of ICAC and VBAC was not significantly (p > 0.05) associated with accelerated brain atrophy. Arteriosclerosis is related to accelerating structural brain changes over time.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.005DOI Listing
September 2021

Lipoprotein(a) is robustly associated with aortic valve calcium.

Heart 2021 09 7;107(17):1422-1428. Epub 2021 May 7.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Objectives: To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC.

Methods: We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC.

Results: The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (β 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase).

Conclusions: Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.
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http://dx.doi.org/10.1136/heartjnl-2021-319044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372399PMC
September 2021

Circulatory markers of immunity and carotid atherosclerotic plaque.

Atherosclerosis 2021 05 7;325:69-74. Epub 2021 Apr 7.

Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. Electronic address:

Background And Aims: We aimed to determine the association of circulatory markers of innate and adaptive immunity with carotid atherosclerotic plaque characteristics.

Methods: In 1602 participants from the population-based Rotterdam Study with subclinicalcarotid atherosclerosis, blood sampling was performed to determine granulocyte, platelet, monocyte (innate immunity) and lymphocyte (adaptive immunity) counts, from which the granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], monocyte-to-lymphocyte ratio [MLR] and systemic immune-inflammation index [SII] were calculated. All participants underwent carotid MRI for evaluation of plaque characteristics. Plaque size (stenosis >30%, maximum plaque thickness) and plaque composition (presence of intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], and calcification) were assessed. Using linear and logistic regression models, the association of innate and adaptive immunity markers with plaque size and plaque components, adjusting for relevant confounders, was assessed.

Results: Higher levels of granulocytes were significantly associated with larger plaque thickness (mean difference [Ln (mm)] per Ln increase granulocyte count [95% CI]: 0.06 [0.02; 0.10]). Conversely, more lymphocytes related with smaller maximum plaque thickness (mean difference [Ln (mm)] per Ln increase lymphocyte count: 0.09 [-0.14;-0.04]) and a lower prevalence of IPH (odds ratio per Ln increase lymphocyte count: 0.60 [0.37; 0.97]). Moreover, all ratio measures were associated with larger plaque thickness, of which the MLR also associated with more frequent LRNC (odds ratio per Ln increase MLR: 1.26 [1.02; 1.56]).

Conclusions: The innate immunity links to larger plaques, whilst the adaptive immunity seems to relate to smaller plaques and a lower frequency of IPH. These results suggest that an imbalance in innate and adaptive immunity may play a role in the vulnerability of carotid atherosclerotic plaques.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.040DOI Listing
May 2021

Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts.

Atherosclerosis 2021 05 3;325:57-62. Epub 2021 Apr 3.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, the Netherlands.

Background And Aims: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit - notably adiposity or insulin resistance - is required, but the association between these risk factors and development of FD has not been studied prospectively.

Methods: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia - likely to be FD - was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated.

Results: Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemia - likely FD - during follow-up. Age-, sex- and cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04-18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia.

Conclusions: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.001DOI Listing
May 2021

Lower complexity and higher variability in beat-to-beat systolic blood pressure are associated with elevated long-term risk of dementia: The Rotterdam Study.

Alzheimers Dement 2021 07 15;17(7):1134-1144. Epub 2021 Apr 15.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Introduction: We hypothesized that subclinical disruption in blood pressure (BP) dynamics, captured by lower complexity and higher variability, may contribute to dementia risk, above and beyond BP levels.

Methods: This prospective cohort study followed 1835 older adults from 1997 to 2016, with BP complexity quantified by sample entropy and BP variability quantified by coefficient of variation using beat-to-beat BP measured at baseline.

Results: Three hundred thirty-four participants developed dementia over 20 years. Reduced systolic BP (SBP) complexity was associated with a higher risk of dementia (hazard ratio [HR] comparing extreme quintiles: 1.55; 95% confidence interval [CI]: 1.09-2.20). Higher SBP variability was also associated with a higher risk of dementia (HR comparing extreme quintiles: 1.57; 95% CI: 1.11-2.22. These findings were observed after adjusting for age, sex, apolipoprotein E (APOE) genotype, mean SBP, and other confounding factors.

Discussions: Our findings suggest that lower complexity and higher variability of beat-to-beat SBP are potential novel risk factors or biomarkers for dementia.
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http://dx.doi.org/10.1002/alz.12288DOI Listing
July 2021

Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events.

J Am Coll Cardiol 2021 03;77(11):1426-1435

Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: Increasing evidence suggests that atherosclerotic plaque composition rather than plaque size is linked to ischemic cardiovascular events, yet largescale population-based data in asymptomatic individuals remain scarce.

Objectives: This study sought to investigate carotid plaque composition in relation to incident stroke and coronary heart disease (CHD) in a population-based setting.

Methods: Between 2007 and 2012, 1,349 persons (mean age 72 years, 49.5% women) from the population-based Rotterdam Study who were free from a history of stroke or CHD, in whom carotid ultrasonography showed subclinical atherosclerosis, and who underwent high-resolution magnetic resonance imaging of the carotid arteries to assess plaque characteristics. These included the presence of specific plaque components (intraplaque hemorrhage [IPH], lipid-rich necrotic core, and calcification), and measures of plaque size (maximum plaque thickness and presence of stenosis of more than 30%). Individuals were continuously followed for the occurrence of stroke or CHD until January 1, 2015. The authors used Cox regression models to assess the association of the plaque characteristics with the incidence of stroke and CHD, with adjustments for age, sex, and cardiovascular risk factors.

Results: During a median of 5.1 years' follow-up for stroke and 4.8 years for CHD, 51 individuals had a stroke and 83 developed CHD. Independent of maximum plaque thickness and cardiovascular risk factors, the presence of IPH was associated with incident stroke and CHD (fully adjusted hazard ratio: 2.42 [95% confidence interval: 1.30 to 4.50], and 1.95 [95% confidence interval: 1.20 to 3.14]). Presence of a lipid-rich necrotic core and calcification were not associated with stroke or CHD.

Conclusions: The presence of IPH in the carotid atherosclerotic plaque is an independent risk factor for stroke and CHD. These findings indicate the promise of IPH as a marker of plaque vulnerability in healthy persons with subclinical atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2021.01.038DOI Listing
March 2021

Prevalence of microvascular angina among patients with stable symptoms in the absence of obstructive coronary artery disease: a systematic review.

Cardiovasc Res 2021 Mar 2. Epub 2021 Mar 2.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Aims: Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities.

Methods And Results: We defined MVA using three definitions: 1. suspected MVA using non-invasive ischemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischemia test result, 2. suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, 3. definitive MVA; proportion of patients with positive ischemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups.Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischemia test, 28% for suspected MVA using specific modalities for MVA and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50.

Conclusions: In patients with stable symptoms of ischemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD.
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http://dx.doi.org/10.1093/cvr/cvab061DOI Listing
March 2021

QTc-interval prolongation and increased risk of sudden cardiac death associated with hydroxychloroquine.

Eur J Prev Cardiol 2020 Nov 22. Epub 2020 Nov 22.

Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Aims: : Hydroxychloroquine and chloroquine ([hydroxy]chloroquine) are drugs used to treat malaria and rheumatological disorders and were recently suggested as beneficial for prevention and treatment of patients with coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection. However, longitudinal studies to assess the electrocardiographic and cardiotoxic effects of these drugs are limited. In this study, we aimed to investigate the effect of these drugs on QTc-interval and incidence of sudden cardiac death (SCD).

Methods: We designed a longitudinal follow-up study of individuals within the prospective population-based Rotterdam Study. Eligible individuals had available data on medication and repeated ECG measurements. The study period was between 1 January 1991 and 1 January 2014. We studied on current and past use of [hydroxy]chloroquine as a time-varying exposure; high versus low daily dose of [hydroxy]chloroquine. QTc-interval duration, and the occurrence of SCD were the main outcomes. SCD was defined as an unexpected and sudden death due to cardiac arrhythmia within one hour of the onset of acute symptoms, and in patients without cardiac symptoms within 24 hours before death.

Results : Among the study population of 14 594 individuals (58.8% women) with an average age of 65 years, 346 patients used [hydroxy]chloroquine at any time during follow-up. The total number of SCD cases was 609. In a multiple linear mixed model analysis, the current use of [hydroxy]chloroquine was associated with a significantly increased duration of the QTc-interval of 8.1 ms (95% CI: 3.6; 12.6) compared with non-users. The association was stronger among current-high daily dosage [15.3 (95%CI: 7.0; 23.6)] compared with current-low daily dosage [5.5 (95%CI: 0.4; 10.7)] users. In a Cox proportional hazard regression analysis, the risk of SCD was significantly higher in participants who were current users of [hydroxy]chloroquine than in non-users [adjusted hazard ratio; 3.7 (95%CI: 1.1; 12.6)].

Conclusions : In this longitudinal study, persons who received [hydroxy]chloroquine had an increased QTc-interval duration and the association was dose-dependent. [Hydroxy]chloroquine was associated with a significantly increased risk of SCD. As long as their activity against COVID-19 is controversial, cardiotoxicity is a strong argument against using these drugs to treat COVID-19 infections.
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http://dx.doi.org/10.1093/eurjpc/zwaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717273PMC
November 2020

Electronic cigarettes and health with special focus on cardiovascular effects: position paper of the European Association of Preventive Cardiology (EAPC).

Eur J Prev Cardiol 2020 Jul 17. Epub 2020 Jul 17.

Department of Community Medicine, The Arctic University of Norway, Norway.

Background: Tobacco use is the single largest preventable risk factor for premature death of non-communicable diseases and the second leading cause of cardiovascular disease. In response to the harmful effects of tobacco smoking, the use of electronic cigarettes (e-cigarettes) has emerged and gained significant popularity over the past 15 years. E-cigarettes are promoted as safe alternatives for traditional tobacco smoking and are often suggested as a way to reduce or quit smoking. However, evidence suggests they are not harmless.

Discussion: The rapid evolution of the e-cigarette market has outpaced the legislator's regulatory capacity, leading to mixed regulations. The increasing use of e-cigarettes in adolescents and young individuals is of concern. While the long-term direct cardiovascular effects of e-cigarettes remain largely unknown, the existing evidence suggests that the e-cigarette should not be regarded as a cardiovascular safe product. The contribution of e-cigarette use to reducing conventional cigarette use and smoking cessation is complex, and the impact of e-cigarette use on long-term cessation lacks sufficient evidence.

Conclusion: This position paper describes the evidence regarding the prevalence of e-cigarette smoking, uptake of e-cigarettes in the young, related legislations, cardiovascular effects of e-cigarettes and the impact of e-cigarettes on smoking cessation. Knowledge gaps in the field are also highlighted. The recommendations from the population science and public health section of the European Association of Preventive Cardiology are presented.
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http://dx.doi.org/10.1177/2047487320941993DOI Listing
July 2020

Heritability analyses of resting heart rate: Is it relevant?

Eur J Prev Cardiol 2020 Jan 20. Epub 2020 Jan 20.

Department of Cardiology, University Medical Center Groningen, The Netherlands.

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http://dx.doi.org/10.1177/2047487319900056DOI Listing
January 2020
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