Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Apoptosis- and necrosis-induced changes in light attenuation measured by optical coherence tomography

Optical coherence tomography (OCT) was used to determine optical properties of pelleted human fibroblasts in which necrosis or apoptosis had been induced. We analysed the OCT data, including both the scattering properties of the medium and the axial point spread function of the OCT system. The optical attenuation coefficient in necrotic cells decreased from 2.2 ± 0.3 mm−1 to 1.3 ± 0.6 mm−1, whereas, in the apoptotic cells, an increase to 6.4 ± 1.7 mm−1 was observed. The results from cultured cells, as presented in this study, indicate the ability of OCT to detect and differentiate between viable, apoptotic, and necrotic cells, based on their attenuation coefficient. This functional supplement to high-resolution OCT imaging can be of great clinical benefit, enabling on-line monitoring of tissues, e.g. for feedback in cancer treatment

Analysis of arterial intimal hyperplasia: review and hypothesis

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign " intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates earl

Measurement of collagen and smooth muscle cell content in atherosclerotic plaques using polarization-sensitive optical coherence tomography

ObjectivesThe purpose of this study was to investigate the measurement of collagen and smooth muscle cell (SMC) content in atherosclerotic plaques using polarization-sensitive optical coherence tomography (PSOCT).BackgroundA method capable of evaluating plaque collagen content and SMC density can provide a measure of the mechanical fidelity of the fibrous cap and can enable the identification of high-risk lesions. Optical coherence tomography has been demonstrated to provide cross-sectional images of tissue microstructure with a resolution of 10 μm. A recently developed technique, PSOCT measures birefringence, a material property that is elevated in tissues such as collagen and SMCs.MethodsWe acquired PSOCT images of 87 aortic plaques obtained from 20 human cadavers. Spatially averaged PSOCT birefringence, Φ, was measured and compared with plaque collagen and SMC content, quantified morphometrically by picrosirius red and smooth muscle actin staining at the corresponding locations.ResultsThere was a high positive correlation between PSOCT measurements of Φ and total collagen content in all plaques (r = 0.67, p < 0.001) and in fibrous caps of necrotic core fibroatheromas (r = 0.68, p < 0.001). Polarization-sensitive optical coherence tomography measurements of Φ demonstrated a strong positive correlation with thick collagen fiber content (r = 0.76, p < 0.001) and SMC density (r = 0.74, p < 0.01).ConclusionsOur results demonstrate that PSOCT enables the measurement of birefringence in plaques and in fibrous caps of necrotic core fibroatheromas. Given its potential to evaluate collagen content, collagen fiber thickness, and SMC density, we anticipate that PSOCT will significantly improve our ability to evaluate plaque stability in patients