Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Smoking is a leading global cause of disease and mortality1. We performed a genomewide meta-analytic association study of smoking-related behavioral traits in a total sample of 41,150 individuals drawn from 20 disease, population, and control cohorts. Our analysis confirmed an effect on smoking quantity (SQ) at a locus on 15q25 (P=9.45e-19) that includes three genes encoding neuronal nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3, CHRNB4). We used data from the 1000 Genomes project to investigate the region using imputation, which allowed analysis of virtually all common variants in the region and offered a five-fold increase in coverage over the HapMap. This increased the spectrum of potentially causal single nucleotide polymorphisms (SNPs), which included a novel SNP that showed the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

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Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome associated with thrombosis. Alternative anticoagulation to heparin is needed for HIT patients during percutaneous coronary intervention (PCI). We evaluated argatroban, a direct thrombin inhibitor, for anticoagulation in this setting. Ninety-one HIT patients underwent 112 PCIs while on intravenous argatroban (25 microg/kg/min [350 microg/kg initial bolus], adjusted to achieve an activated clotting time of 300-450 sec). Primary efficacy endpoints were subjective assessments of the satisfactory outcome of the procedure and adequate anticoagulation during PCI. Among patients undergoing initial PCIs with argatroban (n = 91), 94.5% had a satisfactory outcome of the procedure and 97.8% achieved adequate anticoagulation. Death (zero patients), myocardial infarction (four patients), or revascularization (four patients) at 24 hr after PCI occurred in seven (7.7%) patients overall. One patient (1.1%) experienced periprocedural major bleeding. For patients who had subsequent hospitalizations (mean separation of 150 days) for repeat PCI using argatroban anticoagulation (n = 21), there were no unsatisfactory outcomes. Overall, outcomes were comparable with those historically reported for heparin. Argatroban therefore is a reasonable anticoagulant option in this setting, where current options are limited.

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

In this contemporary prospective multicenter trial of PTCA in the setting of acute coronary syndromes, there was a low incidence of in-hospital clinical events for both treatment groups. The cohort receiving the nonionic dimer iodixanol experienced a 45% reduction in in-hospital MACE when compared with the cohort receiving ioxaglate.

Background The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results We performed a prospective cohort study of subjects ≥ 65 years of age undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists pre-operatively and post-operatively, and underwent post-operative magnetic resonance imaging (MRI). Over a 4 year period, 196 subjects were enrolled at 2 sites. Mean age = 75.8 ± 6.2 years, 36% female, 6% non-white. Clinical strokes were detected in 17%, Transient Ischemic Attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery (STS) database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale (NIHSS) was 3 (interquartile range 1 – 9). Clinical stroke was associated with increased length of stay, median 12 vs 10 days, p = 0.02. Moderate or severe stroke (NIHSS ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality, 38% vs 4%, p = 0.005. Of the 109 stroke-free subjects with post-operative MRI, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions Clinical stroke after AVR was more common than previously reported, more than double for this same cohort in the STS database, and silent cerebral infarctions were detected in over half of patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.