Genome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into... Show moreGenome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analysed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs.\nWe applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with single-cell RNA sequencing (scRNA-seq) data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease (CAD) loci demonstrated a prominent signal in plaque smooth muscle cells (SMCs) (SKI, KANK2, and SORT1) P-adj. = 0.0012, and endothelial cells (ECs) (SLC44A1, ATP2B1) P-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels.\nWe discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with CAD reveal prominent association levels in mainly plaque SMC and EC populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits. Show less
This thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to... Show moreThis thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to investigate such questions in populations underrepresented in clinical trials, such as patients with advanced chronic kidney disease (CKD).The first part of this thesis deals with how to appropriately use routinely collected data to answer causal questions. It illustrates what study designs eliminate commonly occurring biases, namely immortal time and prevalent user bias, and how to use propensity scores to correctly adjust for confounding in the setting of time-fixed and time-varying treatments.The second part investigates the effectiveness and safety of various treatments. For instance, the effectiveness of beta-blockers in patients with heart failure and advanced CKD is investigated. Renin-angiotensin system inhibitors (RASi) are an especially widely used medication class in CKD patients. The relationship between the magnitude of renal function decline - which is commonly observed after initiation of these drugs - with mortality and cardiorenal outcomes is investigated. In addition, comparative effectiveness study of RASi and calcium channel blockers among patients with advanced CKD is performed. In the last two chapters, a target trial is explicitly emulated to investigate the effect of stopping or continuing RASi and the optimal timing to start dialysis in patients with advanced chronic kidney disease. Show less
Objective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at... Show moreObjective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at external validation. Study Design and Setting: We evaluated risk of bias (ROB) on 102 CPMs from the Tufts CPM Registry, comparing PROBAST to a short form consisting of six PROBAST items anticipated to best identify high ROB. We then applied the short form to all CPMs in the Registry with at least 1 validation (n = 556) and assessed the change in discrimination (dAUC) in external validation cohorts (n = 1,147). Results: PROBAST classified 98/102 CPMS as high ROB. The short form identified 96 of these 98 as high ROB (98% sensitivity), with perfect specificity. In the full CPM registry, 527 of 556 CPMs (95%) were classified as high ROB, 20 (3.6%) low ROB, and 9 (1.6%) unclear ROB. Only one model with unclear ROB was reclassified to high ROB after full PROBAST assessment of all low and unclear ROB models. Median change in discrimination was significantly smaller in low ROB models (dAUC -0.9%, IQR -6.2-4.2%) compared to high ROB models (dAUC -11.7%, IQR -33.3-2.6%; P < 0.001). Conclusion: High ROB is pervasive among published CPMs. It is associated with poor discriminative performance at validation, supporting the application of PROBAST or a shorter version in CPM reviews. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http:// creativecommons.org/ licenses/ by- nc- nd/ 4.0/ ) Show less
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have... Show moreCardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options. Show less
Background and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles... Show moreBackground and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two & times; two design with the group with genetically-influenced high TG and LDL-C as a reference. Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 & times; 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction. Show less
Aims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70... Show moreAims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70 years in four geographical risk regions.Methods and results Sex-specific competing risk-adjusted models for estimating CVD risk (CVD mortality, myocardial infarction, or stroke) were derived in individuals aged over 65 without pre-existing atherosclerotic CVD from the Cohort of Norway (28 503 individuals, 10 089 CVD events). Models included age, smoking status, diabetes, systolic blood pressure, and total- and high-density lipoprotein cholesterol. Four geographical risk regions were defined based on country-specific CVD mortality rates. Models were recalibrated to each region using region-specific estimated CVD incidence rates and risk factor distributions. For external validation, we analysed data from 6 additional study populations {338 615 individuals, 33 219 CVD validation cohorts, C-indices ranged between 0.63 [95% confidence interval (CI) 0.61-0.65] and 0.67 (0.64-0.69)}. Regional calibration of expected-vs.-observed risks was satisfactory. For given risk factor profiles, there was substantial variation across the four risk regions in the estimated 10-year CVD event risk.Conclusions The competing risk-adjusted SCORE2-OP model was derived, recalibrated, and externally validated to estimate 5- and 10-year CVD risk in older adults (aged 70 years or older) in four geographical risk regions. These models can be used for communicating the risk of CVD and potential benefit from risk factor treatment and may facilitate shared decision-making between clinicians and patients in CVD risk management in older persons. Show less
Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals... Show moreAims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. Show less
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by... Show moreProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by lowering circulating very low density lipoprotein (VLDL)-cholesterol. We hypothesized that the therapeutic effectiveness of PCSK9 inhibition can be increased by accelerating the generation of VLDL remnants, which typically have a high affinity for the LDLR. Therefore, we aimed to investigate whether accelerating lipolytic processing of VLDL by brown fat activation can further lower (V)LDL and reduce atherosclerosis on top of PCSK9 inhibition. APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the anti-PCSK9 antibody alirocumab or saline. After 2 weeks, both groups of mice were randomized to receive either the selective beta 3-adrenergic receptor (AR) agonist CL316,243 to activate brown fat or saline for 3 additional weeks to evaluate VLDL clearance or 12 additional weeks to analyze atherosclerosis development. beta 3-AR agonism and alirocumab combined decreased (V)LDL-cholesterol compared to alirocumab alone, which was explained by an accelerated plasma clearance of VLDL-cholesteryl esters that were mainly taken up by the liver. In addition, the combination promoted the transfer of VLDL-phospholipids to HDL to a higher extent than alirocumab alone, accompanied by higher plasma HDL-cholesterol levels and increased cholesterol efflux capacity. Consequently, combination treatment largely reduced atherosclerotic lesion area compared to vehicle. Together, beta 3-AR agonism enhances the lipoprotein-modulating effects of alirocumab to further improve dyslipidemia and non-significantly further attenuate atherosclerosis development. Our findings demonstrate that brown fat activation may enhance the therapeutic effects of PCSK9 inhibition in dyslipidemia. Show less
Background Aortic stiffness, assessed through pulse wave velocity (PWV), is an independent predictor for cardiovascular disease risk. However, the scarce availability of normal and reference values... Show moreBackground Aortic stiffness, assessed through pulse wave velocity (PWV), is an independent predictor for cardiovascular disease risk. However, the scarce availability of normal and reference values for cardiovascular magnetic resonance imaging (CMR) based PWV is limiting clinical implementation. The aim of this study was to determine normal and reference values for CMR assessed PWV in the general population. Methods From the 2,484 participants of the Netherlands Epidemiology of Obesity (NEO) study that have available CMR-PWV data, 1,394 participants free from cardiovasculard disease, smokers or treatment for diabetes, hypertension or dyslipidaemia were selected (45-65 years, 51% female). Participants were divided into sex, age and blood pressure (BP) subgroups. Normal values were specified for participants with a BP < 130/80 mmHg and reference values for elevated BP subgroups (>= 130/80 and < 140/90 mmHg; and >= 140/90 mmHg). Differences between groups were tested with independent samples t-test or ANOVA. Due to an oversampling of obese individuals in this study, PWV values are based on a weighted analysis making them representative of the general population. Results Normal mean PWV was 6.0 m/s [95% CI 5.8-6.1]. PWV increased with advancing age and BP categories (both p < 0.001). There was no difference between sex in normal PWV, however in the BP > 140/90 mmHg women had a higher PWV (p = 0.005). The interpercentile ranges were smaller for participants < 55 years old compared to participants >= 55 years, indicating an increasing variability of PWV with age. PWV upper limits were particularly elevated in participants >= 55 years old in the high blood pressure subgroups. Conclusion This study provides normal and reference values for CMR-assessed PWV per sex, age and blood pressure category in the general population. Show less
Background Hospitalised COVID-19 patients with underlying cardiovascular disease (CVD) and cardiovascular risk factors appear to be at risk of poor outcome. It is unknown if these patients should... Show moreBackground Hospitalised COVID-19 patients with underlying cardiovascular disease (CVD) and cardiovascular risk factors appear to be at risk of poor outcome. It is unknown if these patients should be considered a vulnerable group in healthcare delivery and healthcare recommendations during the COVID-19 pandemic. Methods A systematic literature search was performed to answer the following question: In which hospitalised patients with proven COVID-19 and with underlying CVD and cardiovascular risk factors should doctors be alert to a poor outcome? Relevant outcome measures were mortality and intensive care unit admission. Medline and Embase databases were searched using relevant search terms until 9 June 2020. After systematic analysis, 8 studies were included. Results Based on the literature search, there was insufficient evidence that CVD and cardiovascular risk factors are significant predictors of mortality and poor outcome in hospitalised patients with COVID-19. Due to differences in methodology, the level of evidence of all studies was graded 'very low' according to the Grading Recommendations Assessment, Development and Evaluation methodology. It is expected that in the near future, two multinational and multicentre European registries (CAPACITY-COVID and LEOSS) will offer more insight into outcome in COVID-19 patients. Conclusion This literature review demonstrated there was insufficient evidence to identify CVD and cardiovascular risk factors as important predictors of poor outcome in hospitalised COVID-19 patients. However, patients with CVD and cardiovascular risk factors remain vulnerable to infectious disease outbreaks. As such, governmental and public health COVID-19 recommendations for vulnerable groups apply to these patients. Show less
Camelo, R.M.; Caram-Deelder, C.; Duarte, B.P.; Moura, M.C.B. de; Costa, N.C.D.; Costa, I.M.; ... ; Bom, J. van der 2021
Since the introduction of episodic and prophylactic treatments with safer factor concentrates, the life expectancy of people with haemophilia (PwH) has improved considerably. Ageing-related... Show moreSince the introduction of episodic and prophylactic treatments with safer factor concentrates, the life expectancy of people with haemophilia (PwH) has improved considerably. Ageing-related diseases such as cardiovascular disease (CVD) have also become more prevalent in PwH. This cross-sectional study aimed to evaluate CVD risk factors and estimate 10-year risk for CVD events among PwH. Male patients >= 30 years were interviewed and examined. Blood tests were performed at the local laboratory. Eighty-two patients were included, of whom 83% had haemophilia A and half had severe disease. Median age at study entry was 43.0 years (interquartile range [IQR], 36.0-51.3). Prevalence of obesity, systemic arterial hypertension (SAH) and diabetes mellitus were 16%, 60% and 16%, respectively. Hypertriglyceridaemia, hypercholesterolaemia and low HDL blood levels were present in 18%, 41% and 30% of patients, respectively. Metabolic syndrome was found in 37%. The Framingham Risk Score showed that 39% of PwH had a high risk of developing cardiovascular events in the following 10 years. We conclude that, in this cohort, PwH have a higher prevalence of SAH when compared with Brazilian men without haemophilia and about two-fifths have a high risk of developing a CVD event in the following 10 years. Show less
Araghi, S.O.; Kiefte-de Jong, J.C.; Dijk, S.C. van; Swart, K.M.A.; Ploegmakers, K.J.; Zillikens, M.C.; ... ; Velde, N. van der 2021
Background & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues.... Show moreBackground & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk.Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 mg) and vitamin-B12 (500 mg) versus placebo (n = 2,919). Primary outcome was verified self reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease.Results: A total of 1,298 individuals (4 4.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic-and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 mmol/l). No age-dependent effects were present.Conclusions: This study supports and extends previous null -findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated. (c) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. Show less
Breeman, L.D.; Keesman, M.; Atsma, D.E.; Chavannes, N.H.; Janssen, V.; Gemert-Pijnen, L. van; ... ; BENEFIT Consortium 2021
Background: Healthy living is key in the prevention and rehabilitation of cardiovascular disease (CVD). Yet, supporting and maintaining a healthy lifestyle is exceptionally difficult and people... Show moreBackground: Healthy living is key in the prevention and rehabilitation of cardiovascular disease (CVD). Yet, supporting and maintaining a healthy lifestyle is exceptionally difficult and people differ in their needs regarding optimal support for healthy lifestyle interventions.Objective: The goals of this study were threefold: to uncover stakeholders' needs and preferences, to translate these to core values, and develop eHealth technology based on these core values. Our primary research question is: What type of eHealth application to support healthy living among people with (a high risk of) CVD would provide the greatest benefit for all stakeholders? Methods: User-centered design principles from the CeHRes roadmap for eHealth development were followed to guide the uncovering of important stakeholder values. Data were synthesized from various qualitative studies (i. e., literature studies, interviews, think-aloud sessions, focus groups) and usability tests (i.e., heuristic evaluation, cognitive walkthrough, think aloud study). We also developed an innovative application evaluation tool to perform a competitor analysis on 33 eHealth applications. Finally, to make sure to take into account all end-users needs and preferences in eHealth technology development, we created personas and a customer journey.Results: We uncovered 10 universal values to which eHealth-based initiatives to support healthy living in the context of CVD prevention and rehabilitation should adhere to (e.g., providing social support, stimulating intrinsic motivation, offering continuity of care). These values were translated to 14 desired core attributes and then prototype designs. Interestingly, we found that the primary attribute of good eHealth technology was not a single intervention principle, but rather that the technology should be in the form of a digital platform disseminating various interventions, i.e., a 'one-stop-shop'.Conclusion: Various stakeholders in the field of cardiovascular prevention and rehabilitation may benefit most from utilizing one personalized eHealth platform that integrates a variety of evidence-based interventions, rather than a new tool. Instead of a one-size-fits-all approach, this digital platform should aid the matchmaking between patients and specific interventions based on personal characteristics and preferences. Show less
Type 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op... Show moreType 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op deze ziekten. Dit komt gedeeltelijk door hun ongunstige lichaamssamenstelling met veel buikvet en vetopslag in organen zoals spieren en lever, wat hun werking verstoort. Het verminderen van overgewicht verlaagt het risico op type 2 diabetes en hart- en vaatziekten. Verminderen van voedselinname en verhogen van het energieverbruik kan hieraan bijdragen. Een veelbelovende aanpak om het energieverbruik te verhogen, is het stimuleren van vet- en suikerverbranding door lichaamseigen bruin vetweefsel. In dit proefschrift onderzochten wij eerst mechanismen die bijdragen aan cardiometabole ziekten in Zuid-Aziaten. Wij observeerden verminderde Wnt signaaltransductie in wit vet van Zuid-Aziaten, wat samenhing met minder insulinegevoeligheid in dit weefsel. Ook vonden wij een andere samenstelling van LDL-deeltjes in Zuid-Aziaten, wat samenhing met een verhoogde neiging van deze deeltjes om samen te klonteren. Daarna onderzochten wij de effectiviteit van geneesmiddelen om bruin vet activiteit te verhogen en de cardiometabole gezondheid te verbeteren. Wij lieten zien dat stimuleren van de beta-adrenerge receptor de stofwisseling verhoogt en vetverbranding door bruin vet stimuleert, echter niet méer dan koudeblootstelling. Ook vonden wij dat GLP-1 receptoragonisme de suikeropname door bruin vet stimuleert, wat mogelijk bijdraagt aan een gunstig effect op het lichaamsgewicht en suiker- en vetstofwisseling. Deze studies hebben bijgedragen aan kennis over risicofactoren voor cardiometabole ziekten en de ontwikkeling van nieuwe therapeutische strategieën om deze ziekten tegen te gaan, vooral in Zuid-Aziaten. Show less
Zonneveld, M.H.; Noordam, R.; Grond, J. van der; Heemst, D. van; Mooijaart, S.P.; Sabayan, B.; ... ; Trompet, S. 2021
We aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in... Show moreWe aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in older individuals at risk of cardiovascular disease. We studied the cross-sectional and longitudinal associations in participants enrolled in the PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk). Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Analyses were performed with multivariable (repeated) linear regression models and adjusted for demographics, cardiovascular risk-factors, and stratified by sex. We included 5623 dementia-free participants (52 % female, mean age 75 years) with a mean BMI of 26.9 (SD = 4.1). In a sub-study, 527 participants underwent brain MRI. At baseline, individuals with a BMI > 30 had a worse performance on the Stroop test (beta 5.0 s, 95 %CI 2.6;7.5) and larger volumes of the amygdala (beta 234 mm(3), 95 %CI 3;464) and hippocampus (beta 590 mm(3), 95 %CI 181;999), independent of intracranial volume and serum leptin levels, compared with individuals with the reference BMI (BMI 18-25 kg/m(2)). Per log ng/mL higher serum leptin, independent of BMI, a 135 mm(3) (95 %CI 2;268) higher volume of the amygdala was found, but no association was observed with cognitive tests nor with other brain volumes. Stratification for sex did not materially change the results. Whereas higher BMI associated with worse cognitive function independent of leptin levels, our study provided evidence that leptin and BMI independently associate with amygdala volume suggesting potential distinct biological associations. Show less
