Background Vascular dysfunction in atherosclerosis and diabetes, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. Methods and Results In mice with genomic instability due to the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1d/− and XpdTTD mice), we explored age-dependent vascular function as compared to wild-type mice. Ercc1d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness and elevated blood pressure at very young age. The vasodilator dysfunction was due to decreased endothelial eNOS levels as well as impaired smooth muscle cell function, which involved phosphodiesterase (PDE) activity. Similar to Ercc1d/− mice, age-related endothelium-dependent vasodilator dysfunction in XpdTTD animals was increased. To investigate the implications for human vascular disease, we explored associations between single nucleotide polymorphisms (SNPs) of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium, and found a significant association of a SNP (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. Conclusions Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans, but with an accelerated progression, as compared to wild type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.

BackgroundAir pollution has consistently been associated with increased morbidity and mortality due to respiratory and cardiovascular disease. Underlying biological mechanisms are not entirely clear, and hemostasis and inflammation are suggested to be involved.ObjectivesOur aim was to study the association of the variation in local concentrations of airborne particulate matter (PM) with aerodynamic diameter < 10 μm, carbon monoxide, nitrogen monoxide, nitrogen dioxide, and ozone with platelet aggregation, thrombin generation, fibrinogen, and C-reactive protein (CRP) levels in healthy individuals.MethodsFrom 40 healthy volunteers, we collected 13 consecutive blood samples within a 1-year period and measured light-transmittance platelet aggregometry, thrombin generation, fibrinogen, and CRP. We performed regression analysis using generalized additive models to study the association between the hemostatic and inflammatory variables, and local environmental concentrations of air pollutants for time lags within 24 hr before blood sampling or 24–96 hr before blood sampling.ResultsIn general, air pollutants were associated with platelet aggregation [average, +8% per interquartile range (IQR), p < 0.01] and thrombin generation (average, +1% per IQR, p < 0.05). Platelet aggregation was not affected by in vitro incubation of plasma with PM. We observed no relationship between any of the air pollutants and fibrinogen or CRP levels.ConclusionsAir pollution increased platelet aggregation as well as coagulation activity but had no clear effect on systemic inflammation. These prothrombotic effects may partly explain the relationship between air pollution and the risk of ischemic cardiovascular disease.

Summary. Background: Concentrations of inflammatory and hemostatic variables are influenced by biological variation, which is the natural within-subject variation over time. Objectives: The aim of this study was to determine fibrinogen, C-reactive protein (CRP), platelet aggregation, thrombin generation and prothrombin time (PT): (i) the number of repeated measurements needed to obtain the true habitual concentration of an individual; (ii) the recommended analytical imprecision for diagnosis and monitoring; (iii) the recommended analytical bias; (iv) the contribution of analytical imprecision to test result variability; (v) the index of individuality; (vi) the reference change value; and (vii) the seasonal variation. Subjects and methods: We collected 520 blood samples over a 1-year period from 40 healthy individuals, and determined the between-subject, within-subject and seasonal variation in fibrinogen, CRP, platelet aggregation, thrombin generation and PT. Results: One or two repeated measurements were sufficient to establish the true habitual concentration, except for platelet aggregation and peak thrombin generation, where at least four and nine repeated measurements were needed, respectively. For diagnosis, the maximal recommended coefficient of analytical variation (CV) was 4%-27%, except for CRP (77.7%). For monitoring, these CVs were on average 3% lower. Recommended analytical bias varied between 1.7% and 33.2%. Finally, seasonal variation was observed in concentrations of fibrinogen and thrombin generation, which could explain approximately 11% of their total variation. Conclusion: This study provides insights into the biological variability of selected inflammatory and hemostatic markers, which can be used for sample size calculations and to determine the analytical quality specifications for their respective assays.

Background-The clinical efficacy of clopidogrel is hampered by a large interindividual variability in platelet inhibition.Polymorphisms in the P2RY12 receptor gene have been suggested to contribute to this variability, but previous studies included a relatively small number of patients and incompletely covered the common variation in the P2RY12 gene. The aim of this study was to comprehensively investigate the possible association between common variation in the entire P2RY12 locus and the magnitude of residual on-clopidogrel platelet reactivity measured by 2 commonly used platelet function assays in a large cohort of patients. Methods and Results-A total of 1031 consecutive patients with coronary artery disease who were scheduled for elective percutaneous coronary interventions were enrolled. Platelet function was assessed by means of ADP-induced light-transmittance aggregometry and the VerifyNow P2Y12 assay. Six haplotype-tagging single nucleotide polymorphisms were carefully selected to comprehensively cover the total common variation in the P2RY12 gene and its flanking regulatory regions. Six common haplotypes were inferred from these haplotype-tagging single nucleotide polymorphisms (denoted A to F). Haplotype F was associated with significantly lower residual on-clopidogrel platelet reactivity compared with the reference haplotype A. The size of this effect per haplotype allele was approximately 5% aggregation in the ADP-induced light-transmittance aggregometry (PϽ0.05) and 11 P2Y12 reaction units in the VerifyNow P2Y12 assay (PϽ0.05). Conclusions-Common