Background and aimsThis study aims to identify sex-specific transcriptional differences and signaling pathways in circulating monocytes contributing to cardiovascular disease.Methods and resultsWe... Show moreBackground and aimsThis study aims to identify sex-specific transcriptional differences and signaling pathways in circulating monocytes contributing to cardiovascular disease.Methods and resultsWe generated sex-biased gene expression signatures by comparing male versus female monocytes of coronary artery disease (CAD) patients (n = 450) from the Center for Translational Molecular Medicine–Circulating Cells Cohort. Gene set enrichment analysis demonstrated that monocytes from female CAD patients carry stronger chemotaxis and migratory signature than those from males. We then inferred cytokine signaling activities based on CytoSig database of 51 cytokine and growth factor regulation profiles. Monocytes from females feature a higher activation level of EGF, IFN1, VEGF, GM-CSF, and CD40L pathways, whereas IL-4, INS, and HMGB1 signaling was seen to be more activated in males. These sex differences were not observed in healthy subjects, as shown for an independent monocyte cohort of healthy subjects (GSE56034, n = 485). More pronounced GM-CSF signaling in monocytes of female CAD patients was confirmed by the significant enrichment of GM–CSF–activated monocyte signature in females. As we show these effects were not due to increased plasma levels of the corresponding ligands, sex-intrinsic differences in monocyte signaling regulation are suggested. Consistently, regulatory network analysis revealed jun-B as a shared transcription factor activated in all female-specific pathways except IFN1 but suppressed in male-activated IL-4.ConclusionsWe observed overt CAD-specific sex differences in monocyte transcriptional profiles and cytokine- or growth factor-induced responses, which provide insights into underlying mechanisms of sex differences in CVD. Show less
Kuneman, J.H.; Hoogen, I.J. van den; Schultz, J.; Maaniitty, T.; Rosendael, A.R. van; Kamperidis, V.; ... ; Knuuti, J. 2023
Background: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis... Show moreBackground: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis that, at patient level, the fraction of non-calcified plaque volume (PV) of total PV is associated with ischemia and outcomes in patients with CAD. This ratio could be a simple and clinically useful parameter, if predicting outcomes. Methods: Consecutive patients with suspected CAD undergoing coronary computed tomography angiography with selective positron emission tomography perfusion imaging were selected. Plaque components were quantitatively analyzed at patient level. The fraction of various plaque components were expressed as percentage of total PV and examined among patients with non-obstructive CAD, suspected stenosis with normal perfusion, and those with reduced myocardial perfusion. Clinical outcomes included all-cause mortality and myocardial infarction. Results: In total, 494 patients (age 63 & PLUSMN; 9 years, 55% male) were included. Total PV and all plaque components were significantly larger in patients with reduced myocardial perfusion compared to patients with normal perfusion and those with non-obstructive CAD. During follow-up 35 events occurred. Patients with any plaque component & GE; median showed worse outcomes (log-rank p < 0.001 for all). In addition, low-attenuation plaque & GE; median was associated with worse outcomes independent of total PV (adjusted HR: 2.754, 95% CI: 1.022-7.0419, p = 0.045). The fractions of the various plaque components were not associated with outcomes. Conclusion: Larger total PV or any plaque component at patient level are associated with abnormal myocardial perfusion and adverse events. The various plaque components as fraction of total PV lack additional prognostic value. Show less
Luo, J.; Noordam, R.; Jukema, J.W.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
Aim: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance... Show moreAim: Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies. Methods and results: Multivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively. Conclusion: Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF. Show less
Luo, J.; Noordam, R.; Jukema, J.W.; Dijk, K.W. van; Hägg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
AimMitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance,... Show moreAimMitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies.Methods and resultsMultivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively.ConclusionOur findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF. Show less
Albalak, G.; Stijntjes, M.; Bodegom, D. van; Jukema, J.W.; Atsma, D.E.; Heemst, D. van; Noordam, R. 2022
Aims Little is known about the impact of daily physical activity timing (here referred to as 'chronoactivity') on cardiovascular disease (CVD) risk. We aimed to examined the associations between... Show moreAims Little is known about the impact of daily physical activity timing (here referred to as 'chronoactivity') on cardiovascular disease (CVD) risk. We aimed to examined the associations between chronoactivity and multiple CVD outcomes in the UK Biobank. Methods and results physical activity data were collected in the UK-Biobank through triaxial accelerometer over a 7-day measurement period. We used K-means clustering to create clusters of participants with similar chronoactivity irrespective of the mean daily intensity of the physical activity. Multivariable-adjusted Cox-proportional hazard models were used to estimate hazard ratios (HRs) comparing the different clusters adjusted for age and sex (model 1), and baseline cardiovascular risk factors (model 2). Additional stratified analyses were done by sex, mean activity level, and self-reported sleep chronotype. We included 86 657 individuals (58% female, mean age: 61.6 [SD: 7.8] years, mean BMI: 26.6 [4.5] kg/m(2)). Over a follow-up period of 6 years, 3707 incident CVD events were reported. Overall, participants with a tendency of late morning physical activity had a lower risk of incident coronary artery disease (HR: 0.84, 95%CI: 0.77, 0.92) and stroke (HR: 0.83, 95%CI: 0.70, 0.98) compared to participants with a midday pattern of physical activity. These effects were more pronounced in women (P-value for interaction = 0.001). We did not find evidence favouring effect modification by total activity level and sleep chronotype. Conclusion Irrespective of total physical activity, morning physical activity was associated with lower risks of incident cardiovascular diseases, highlighting the potential importance of chronoactivity in CVD prevention. Show less
Schultz, J.; Hoogen, I.J. van den; Kuneman, J.H.; Graaf, M.A. de; Kamperidis, V.; Broersen, A.; ... ; Knuuti, J. 2022
Endothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed... Show moreEndothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed tomography angiography (CCTA)-based ESS in coronary arteries without atherosclerosis, and to assess factors affecting ESS values. CCTA images from patients with suspected coronary artery disease were analyzed to identify coronary arteries without atherosclerosis. Minimal and maximal ESS values were calculated for 3-mm segments. Factors potentially affecting ESS values were examined, including sex, lumen diameter and distance from the ostium. Segments were categorized according to lumen diameter tertiles into small (< 2.6 mm), intermediate (2.6-3.2 mm) or large (>= 3.2 mm) segments. A total of 349 normal vessels from 168 patients (mean age 59 +/- 9 years, 39% men) were included. ESS was highest in the left anterior descending artery compared to the left circumflex artery and right coronary artery (minimal ESS 2.3 Pa vs. 1.9 Pa vs. 1.6 Pa, p < 0.001 and maximal ESS 3.7 Pa vs. 3.0 Pa vs. 2.5 Pa, p < 0.001). Men had lower ESS values than women, also after adjusting for lumen diameter (p < 0.001). ESS values were highest in small segments compared to intermediate or large segments (minimal ESS 3.8 Pa vs. 1.7 Pa vs. 1.2 Pa, p < 0.001 and maximal ESS 6.0 Pa vs. 2.6 Pa vs. 2.0 Pa, p < 0.001). A weak to strong correlation was found between ESS and distance from the ostium (rho = 0.22-0.62, p < 0.001). CCTA-based ESS values increase rapidly and become widely scattered with decreasing lumen diameter. This needs to be taken into account when assessing the added value of ESS beyond lumen diameter in highly stenotic lesions. Show less
Rosendael, S.E. van; Kuneman, J.H.; Hoogen, I.J. van den; Kitslaar, P.H.; Rosendael, A.R. van; Bijl, P. van der; ... ; Bax, J.J. 2022
Pericoronary adipose tissue (PCAT) attenuation, derived from coronary computed tomography angiography (CCTA), is associated with coronary artery inflammation. Values for PCAT attenuation in men and... Show morePericoronary adipose tissue (PCAT) attenuation, derived from coronary computed tomography angiography (CCTA), is associated with coronary artery inflammation. Values for PCAT attenuation in men and women without atherosclerosis on CCTA are lacking. The aim of the current study was to assess the mean PCAT attenuation in individuals without coronary artery atherosclerosis on CCTA. Data on PCAT attenuation in men and women without coronary artery atherosclerosis on CCTA were included in this retrospective analysis. The PCAT attenuation was analyzed from the proximal part of the right coronary artery (RCA), the left anterior descending artery (LAD), and the left circumflex artery (LCx). For patient level analyses the mean PCAT attenuation was defined as the mean of the three coronary arteries. In 109 individuals (mean age 45 +/- 13 years; 44% men), 320 coronary arteries were analyzed. The mean PCAT attenuation of the overall population was - 64.4 +/- 8.0 HU. The mean PCAT attenuation was significantly lower in the LAD compared with the LCx and RCA (- 67.8 +/- 7.8 HU vs - 62.6 +/- 6.8 HU vs - 63.6 +/- 7.9 HU, respectively, p < 0.001). In addition, the mean PCAT attenuation was significantly higher in men vs. women in all three coronary arteries (LAD: - 65.7 +/- 7.6 HU vs - 69.4 +/- 7.6 HU, p = 0.014; LCx: - 60.6 +/- 7.4 HU vs - 64.3 +/- 5.9 HU, p = 0.008; RCA: -61.7 +/- 7.9 HU vs - 65.0 +/- 7.7 HU, p = 0.029, respectively). The current study provides mean PCAT attenuation values, derived from individuals without CAD. Moreover, the mean PCAT attenuation is lower in women vs. men. Furthermore, the mean PCAT attenuation is significantly lower in the LAD vs LCx and RCA. Show less
Objectives To present an overview of studies using serial coronary computed tomography angiography (CCTA) as a tool for finding both quantitative (changes) and qualitative plaque characteristics as... Show moreObjectives To present an overview of studies using serial coronary computed tomography angiography (CCTA) as a tool for finding both quantitative (changes) and qualitative plaque characteristics as well as epicardial adipose tissue (EAT) volume changes as predictors of plaque progression and/or major adverse cardiac events (MACE) and outline the challenges and advantages of using a serial non-invasive imaging approach for assessing cardiovascular prognosis. Methods A literature search was performed in PubMed, Embase, Web of Science, Cochrane Library and Emcare. All observational cohort studies were assessed for quality using the Newcastle-Ottawa Scale (NOS). The NOS score was then converted into Agency for Healthcare Research and Quality (AHRQ) standards: good, fair and poor. Results A total of 36 articles were analyzed for this review, 3 of which were meta-analyses and one was a technical paper. Quantitative baseline plaque features seem to be more predictive of MACE and/or plaque progression as compared to qualitative plaque features. Conclusions A critical review of the literature focusing on studies utilizing serial CCTA revealed that mainly quantitative baseline plaque features and quantitative plaque changes are predictive of MACE and/or plaque progression contrary to qualitative plaque features. Significant questions regarding the clinical implications of these specific quantitative and qualitative plaque features as well as the challenges of using serial CCTA have yet to be resolved in studies using this imaging technique. Show less
Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed... Show moreBackground Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk. Show less
Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in... Show moreAims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1 beta can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.[GRAPHICS]. Show less
Introduction Coronary angiography (CAG) is the standard modality for assessment of coronary stenoses and intraprocedural guidance of percutaneous coronary interventions (PCI). However, the... Show moreIntroduction Coronary angiography (CAG) is the standard modality for assessment of coronary stenoses and intraprocedural guidance of percutaneous coronary interventions (PCI). However, the limitations of CAG are well recognized. Intracoronary imaging (ICI) can potentially overcome these limitations. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the main ICI techniques utilized in clinical practice. Aim This narrative literature review addresses the current clinical applications of OCT in relation to IVUS and CAG in patients with coronary artery disease (CAD). Items reviewed are: technical implications of OCT and IVUS, lesion characterization and decision-making, stent optimization criteria, post-stenting results, safety in terms of procedural complications, clinical outcomes, and indications. Main Findings OCT is able to reveal more detail than IVUS due to its higher resolution. However, this higher resolution comes at the cost of a lower penetration depth. Pre-stenting OCT results in procedural change in more than 50% of the cases in terms of stent length and diameter. Post-stenting OCT resulting in stent optimization is reported in at least 27% of the cases. Malapposition and under-expansion are treated with post-dilatations, while edge dissections are treated with additional stent placement. Stent expansion, stent apposition, distal stent edge dissections, and reference lumen areas seem to be the most important stent optimization criteria for both decision-making and for reducing the risk of adverse events during follow-up. Both OCT and IVUS are superior in terms of post-stenting results compared with CAG alone. However, there is no consensus about whether OCT guidance results in better stent expansion than IVUS guidance. OCT, IVUS, and CAG are safe procedures with few reported procedural complications. In general, OCT guidance seems to contribute to favorable clinical outcomes compared with CAG guidance only. However, OCT guidance results in similar clinical outcomes as with IVUS guidance. OCT could be considered for lumen assessment and stent-related morphology in more complex cases in which CAG interpretation remains uncertain. Since OCT and IVUS have distinct characteristics, these techniques are complementary and should be considered carefully for each patient case based on the benefits and limitations of both techniques. Show less
BackgroundWe need new biomarkers that can predict cardiovascular disease to improve both diagnosis and therapeutic strategies. The CIRCULATING CELLS study was designed to study the role of several... Show moreBackgroundWe need new biomarkers that can predict cardiovascular disease to improve both diagnosis and therapeutic strategies. The CIRCULATING CELLS study was designed to study the role of several cellular mediators of atherosclerosis as biomarkers of coronary artery disease (CAD). An objective and reproducible method for the quantification of CAD extension is required to establish relationships with these potential biomarkers. We sought to analyse the correlation of the SYNTAX score with known CAD risk factors to test it as a valid marker of CAD extension.Methods and resultsA subgroup of 279 patients (67.4% males) were included in our analysis. Main exclusion criteria were a history of previous percutaneous coronary intervention or surgical revascularisation that prevent an accurate assessment of the SS. Diabetes mellitus, smoking, renal insufficiency, body mass index and a history of CAD and myocardial infarction were all positively and strongly associated with a higher SYNTAX score after adjustment for the non-modifiable biological factors (age and sex). In the multivariate model, age and male sex, along with smoking and renal insufficiency, remain statistical significantly associated with the SYNTAX score.ConclusionIn a selected cohort of revascularisation-naive patients with CAD undergoing coronary angiography, non-modifiable cardiovascular risk factors such as advanced age, male sex, as well as smoking and renal failure were independently associated with CAD complexity assessed by the SYNTAX score. The SYNTAX score may be a valid marker of CAD extension to establish relationships with potential novel biomarkers of coronary atherosclerosis.Keywords: Coronary artery disease, Coronary angiography, Risk assessment, Risk factors Show less
Elsenberg, E.H.A.M.; Sels, J.E.M.; Hillaert, M.A.; Schoneveld, A.H.; Dungen, N.A.M. van den; Holten, T.C. van; ... ; Hoefer, I.E. 2013
