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BACKGROUND: Acquired loss of the largest von Willebrand factor multimers is a common hemostatic disturbance in patients with aortic valve stenosis (AS), resulting in impaired platelet adhesion and increased bleeding risk. AS is also associated with atherosclerosis and myocardial infarction (MI). Our aim was to study the clinical outcomes associated with AS in MI patients treated with dual antiplatelet therapy (DAPT) in a nationwide hospital-based register study.METHODS: Based on nationwide hospital discharge registers from Sweden (2005-2010) and Denmark (2005-2015), we calculated 1-year incidence rates and hazard ratios of bleeding, recurrent MI, and all-cause mortality in MI patients with and without AS treated with DAPT. Results from both countries were also combined in a meta-analysis.RESULTS: We included 50,460 MI patients from Sweden and 50,307 MI patients from Denmark, of which 3% had AS. The bleeding rates (per 100 person-years) in Sweden and Denmark were 3.2 and 3.3 among patients without AS vs. 9.2 and 8.3 among patients with AS. All-cause mortality rates were 7.1 vs. 28.7 in Sweden and 5.8 vs. 30.7 in Denmark among patients without and with AS, respectively. Patients with AS had an increased risk of bleeding, recurrent MI and all-cause mortality. Combined results from both countries were similar for bleeding (hazard ratio 1.59 [0.98-2.59]), recurrent MI (1.78 [1.25-2.54]), and all-cause mortality (1.76 [1.26-2.47]).CONCLUSION: AS was associated with an increased risk of bleeding, recurrent MI and mortality after MI when treated with DAPT. Individualized selection of antiplatelet therapy may be warranted in this high-risk population.

BACKGROUND: The heritability of venous thromboembolism (VTE) is only partially explained by variants in 17 previously VTE-associated genes. OBJECTIVE: This article screens for additional rare variants in the 17 genes and investigates the relative contributions of pro- and anticoagulant genes to VTE. PATIENTS AND METHODS: Ninety-six VTE patients from the population-based Malmö Thrombophilia Study were analysed using an AmpliSeq strategy and Ion Torrent sequencing and the variant data were compared with data from public databases. RESULTS: A total of 102 non-synonymous and 76 synonymous variants were identified. Forty-six non-synonymous variants were present in the human gene mutation database. Anticoagulant and procoagulant genes showed 14 and 22 rare non-synonymous variants, respectively. Individual patients showed varying numbers of risk factors; 13 patients had non-synonymous mutations in SERPINC1, PROC and PROS1 genes and 42 had factor V Leiden or prothrombin mutations generating a total of 47 patients with at least one of these risk factors. Ten common VTE-associated variants showed low level enrichments and no correlation to the other risk factors. The enrichment of previously identified risk factors was similar to previous studies. Determination of the nsyn/syn ratio (number of non-synonymous variants per non-synonymous site, nsyn, to the number of synonymous variants per synonymous site, syn) showed, as expected in patients, an increase of non-synonymous relative to synonymous anticoagulant variants compared with controls (nsyn/syn, 0.95 vs. 0.68). In contrast, non-synonymous procoagulant variants (nsyn/syn, 0.31 vs. 0.63) showed a decrease. We suggest that the deficit of non-synonymous variants in procoagulant genes is a novel mechanism contributing to VTE.

Aims Middle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of rst-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described. Methods Citizens of Malmö, Sweden, aged 30–75 years born in Iraq or Sweden were invited to participate in this population- based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests. Results In total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had ≥ 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH− 29.4%; FH+ 38.8%; FH++ 61.7%) without signi cant di erences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of ≥ 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion. Conclusions The Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with ≥ 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden in uences insulin secretion to a higher degree than insulin action and may be a logical target for intervention.

Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.