Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of... Show moreAtherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naive Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome. Show less
An early invasive strategy in patients who have acute coronary syndrome without ST-elevation (NSTE-ACS) can improve clinical outcome in high-risk subgroups. According to the current guidelines of... Show moreAn early invasive strategy in patients who have acute coronary syndrome without ST-elevation (NSTE-ACS) can improve clinical outcome in high-risk subgroups. According to the current guidelines of the European Society of Cardiology (ESC), the majority of NSTE-ACS patients are classified as "high-risk". We propose to prioritise patients with a global registry of acute coronary events (GRACE) risk score >140 over patients with isolated troponin rise or electrocardiographic changes and a GRACE risk score <140. We also acknowledge that same-day transfer for all patients at a high risk is not necessary in the Netherlands since the majority of Dutch cardiology departments are equipped with a catheterisation laboratory where diagnostic coronary angiography is routinely performed in NSTE-ACS patients. Therefore, same-day transfer should be restricted to true high-risk patients (in addition to those NSTE-ACS patients with very high-risk (VHR) criteria) in centres without coronary angiography capabilities. Show less
BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising... Show moreBACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development. Show less
BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of... Show moreBACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators. Show less
Aims Monocytes contribute to arteriogenesis by infiltration to sites of collateral growth and subsequent production and release of growth factors. Transforming growth factor beta 1 (TGF-beta 1)... Show moreAims Monocytes contribute to arteriogenesis by infiltration to sites of collateral growth and subsequent production and release of growth factors. Transforming growth factor beta 1 (TGF-beta 1) mediates monocyte motility and stimulates arteriogenesis. TGF-beta 1 signalling mechanisms mediating monocyte motility are unknown so far. Moreover, the influence of cardiovascular risk factor diabetes on TGF-beta 1-induced monocyte migration remains to be elucidated. Methods and results Stimulation of primary human monocytes with TGF-beta 1 endorsed phosphorylation of v-Akt murine thymoma viral oncogene analogues protein (AKT), p38, and extracellular signal-related kinase 1/2 (ERK1/2), besides the activation of the SMA/MAD homologues protein (SMAD) pathway. Inhibition of the TGF-btype 1 receptor, alias activin receptor-like kinase 5 (ALK5), hindered monocyte chemotaxis towards TGF-beta 1 and TGF-beta 1-activated downstream signalling cascades. Individual genetic knock-downs for receptor-regulated SMAD2 and SMAD3 did not affect monocyte migration to TGF-beta 1. Inhibition of phosphoinositide 3 kinase (PI3K) activity, but not AKT, diminished both basal and TGF-beta 1-mediated monocyte motility. TGF-beta 1-induced monocyte chemotaxis did not rely on ERK1/2, but rather on p38. Remarkably, TGF-beta 1 was able to stimulate chemotaxis of diabetic monocytes. Conclusion The current study provides novel insights into the molecular mechanisms of TGF-beta 1-induced monocyte migration, requiring ALK5 kinase activity and signalling via PI3K and p38. TGF-beta 1-driven monocyte motogenicity is fully functional in diabetic conditions, which is in sharp contrast to the impaired chemotactic responses to certain other arteriogenic cytokines. Therefore, TGF-beta 1 may be a promising candidate for endogenously and exogenously stimulating collateral growth in diabetic patients. Show less
Hirsch, A.; Nijveldt, R.; Vleuten, P.A. van der; Tijssen, J.G.P.; Giessen, W.J. van der; Tio, R.A.; ... ; HEBE Investigators 2011
Background: Magnetic resonance imaging (MRI) is sensitive to early atherosclerotic changes such as positive remodeling in patients with coronary artery disease (CAD). We assessed prevalence,... Show moreBackground: Magnetic resonance imaging (MRI) is sensitive to early atherosclerotic changes such as positive remodeling in patients with coronary artery disease (CAD). We assessed prevalence, quality, and extent of coronary atherosclerosis in a group of healthy subjects compared to patients with confirmed CAD. Methodology: Twenty-two patients with confirmed CAD (15M, 7F, mean age 60.4 +/- 10.4 years) and 26 healthy subjects without history of CAD (11M, 15F, mean age 56.1 +/- 4.4 years) underwent MRI of the right coronary artery (RCA) and vessel wall (MR-CVW) on a clinical 1.5T MR-scanner. Wall thickness measurements of both groups were compared. Principal Findings: Stenoses of the RCA (both < and >= 50% on CAG) were present in all patients. In 21/22 patients, stenoses detected at MRI corresponded to stenoses detected with conventional angiography. In 19/26 asymptomatic subjects, there was visible luminal narrowing in the MR luminography images. Fourteen of these subjects demonstrated corresponding increase in vessel wall thickness. In 4/26 asymptomatic subjects, vessel wall thickening without luminal narrowing was present. Maximum and mean wall thicknesses in patients were significantly higher (2.16 vs 1.92 mm, and 1.38 vs 1.22 mm, both p < 0.05). Conclusions: In this cohort of middle-aged individuals, both patients with stable angina and angiographically proven coronary artery disease, as well as age-matched asymptomatic subjects. exhibited coronary vessel wall thickening detectable with MR coronary vessel wall imaging. Maximum and mean wall thicknesses were significantly higher in patients. The vast majority of asymptomatic subjects had either positive remodeling without luminal narrowing, or non-significant stenosis. Show less
Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been... Show moreObjective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis. Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted. Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Show less
