HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Are air pollution and traffic noise independently associated with atherosclerosis: the Heinz Nixdorf Recall Study

Living close to high traffic has been linked to subclinical atherosclerosis, however it is not clear, whether fine particulate matter (PM) air pollution or noise, two important traffic-related exposures, are responsible for the association. We investigate the independent associations of long-term exposure to fine PM and road traffic noise with thoracic aortic calcification (TAC), a reliable measure of subclinical atherosclerosis. We used baseline data (20002003) from the German Heinz Nixdorf Recall Study, a population-based cohort of 4814 randomly selected participants. We assessed residential long-term exposure to PM with a chemistry transport model, and to road traffic noise using faade levels from noise models as weighted 24 h mean noise (L-den) and night-time noise (L-night). Thoracic aortic calcification was quantified from non-contrast enhanced electron beam computed tomography. We used multiple linear regression to estimate associations of environmental exposures with ln(TAC1), adjusting for each other, individual, and neighbourhood characteristics. In 4238 participants (mean age 60 years, 49.9 male), PM2.5 (aerodynamic diameter 2.5 m) and L-night are both associated with an increasing TAC-burden of 18.1 (95 CI: 6.6; 30.9) per 2.4 g/m(3) PM2.5 and 3.9 (95 CI 0.0; 8.0) per 5dB(A) L-night, respectively, in the full model and after mutual adjustment. We did not observe effect measure modification of the PM2.5 association by L-night or vice versa. Long-term exposure to fine PM and night-time traffic noise are both independently associated with subclinical atherosclerosis and may both contribute to the association of traffic proximity with atherosclerosis

Coronary artery calcium score improves cardiovascular risk prediction in persons without indication for statin therapy.

BACKGROUND: Recent revision to the Canadian Cardiovascular Society (CCS) guidelines on cardiovascular disease (CVD) risk stratification provides expanded recommendations for statin therapy. If CVD risk in the remaining individuals can further be stratified and discriminated by additional risk assessment using coronary artery calcium (CAC) scoring is unknown. METHODS AND RESULTS: In a retrospectively analyzed subgroup comprising 1934 participants from the Heinz Nixdorf Recall study, who did not meet criteria for statin therapy based on current CCS guidelines, traditional CVD risk variables and CAC were measured. Between 2000 and 2008, incident CVD events, i.e. coronary deaths, non-fatal myocardial infarction, coronary revascularization, stroke and CV death were determined. Those 43 participants who experienced 55 CVD events (5-year risk to first event: 2.2% (1.6-3.0%)) had higher CAC scores than those who did not (p<0.0001). In multiple Cox regression analysis including age, sex, total-/HDL-cholesterol ratio, and antihypertensive medication, log2(CAC+1) remained an independent predictor of CVD events (HR=1.21 (1.09-1.33), p<0.001). Measures of discrimination improved with the addition of CAC into the model: the incremental discrimination improvement was 0.0167, p=0.014. Net reclassification improvement using risk categories of 0-<3%, 3-10% and >10% was 25.1%, p=0.01, largely driven by a 32.6% correct up-classification in persons with events. Yet, only 38 (2%) of participants were identified being at high risk using CAC imaging in addition to traditional risk factor assessment. CONCLUSION: Adding CAC to traditional risk assessment in persons without indication for statin therapy improves discrimination. However, reclassification to the high risk category and overall event rates seem too low to justify liberal CAC testing in all these individuals

In vivo effects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

15-Deoxyspergualin (DSG) is an alternative treatment modality for Wegener’s granulomatosis (WG) patients refractory to conventional treatment. Nevertheless, it is unclear how DSG modulates disease activity in these patients. This study was conducted to investigate which parameters of adaptive and acquired immunity were influenced during two subsequent cycles of DSG treatment. Emphasis was put upon T cell and monocyte activation, neutrophil function and surface expression of proteinase-3 (PR-3). Anti-CD3/anti-CD28 and interleukin (IL)-15/IL-7-mediated T cell proliferation were assessed by fluorescence activated cell sorter (FACS) analysis using carboxyfluorescein succinimidyl ester (CSFE) labelling. Interferon (IFN)-γ and IL-10 production were determined in the supernatants of these cultures by enzyme-linked immunosorbent assay. Monocyte activation was assessed in lipopolysaccharide (LPS)-stimulated whole blood, using tumour necrosis factor (TNF)-α as read-out. Neutrophil function was determined by measuring oxidative burst, chemotaxis and phagocytosis. T cell activation markers and PR3 expression were measured by FACS. All parameters were determined directly before and after each DSG cycle. Anti-CD3/anti-CD28-mediated T cell proliferation was reduced directly after DSG treatment. Directly before a subsequent cycle of DSG was started, T cell proliferation was increased. Similar findings were observed for IFN-γ and IL-10 production by T cells. DSG did not influence IL-15/IL-7-mediated T cell proliferation. LPS-mediated TNF-α production was also impaired directly after DSG treatment. No influence on T cell activation markers, neutrophil function and surface PR-3 expression was observed in peripheral blood of these patients. Our data demonstrate that DSG influences T cell and monocyte activation in a reversible fashion. Although DSG causes neutropenia in these patients, it does not influence neutrophil function