Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta‐analysis

Summary. Background: Whether patients with unprovoked venous thromboembolism (VTE) have a higher risk of arterial cardiovascular events than the general population and patients with provoked VTE is a matter of debate. Objective: To perform a systematic review and a meta‐analysis aimed at assessing the risk of arterial cardiovascular events in patients with unprovoked VTE as compared with both patients with provoked VTE and controls. Methods: A systematic search was performed. Studies reporting on (i) patients with confirmed VTE, (ii) a follow‐up of at least 6 months and (iii) the incidence of arterial cardiovascular events (acute myocardial infarction and ischemic stroke) were included in the systematic review. Those studies reporting separate incidences of cardiovascular events in patients with unprovoked and provoked VTE or patients with unprovoked VTE and controls were included in the incidence rate meta‐analysis. Results: Overall, 17 studies were included in the systematic review. The weighted mean incidence of arterial cardiovascular events was 0.46% [95% confidence interval (CI) 0.34–0.59] and 0.35% (95% CI 0.24–0.49) per patient‐year in patients with unprovoked and provoked VTE, respectively. Six studies were included in the meta‐analysis. The risk of arterial cardiovascular events appeared to be higher in patients with unprovoked VTE than in controls [incidence rate ratio (IRR) 1.87, 95% CI 1.32–2.65] and than in patients with provoked VTE (IRR 1.86, 95% CI 1.19–2.89). Conclusions: Patients with unprovoked VTE have a higher risk of arterial cardiovascular events than patients with provoked VTE over long‐term follow‐up.     

Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review

Summary. It is well established that high plasma von Willebrand factor (VWF) levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and ischemic stroke. As plasma VWF levels are, to a large extent, genetically determined, numerous association studies have been performed to assess the effect of genetic variability in the VWF gene (VWF) on VWF antigen and activity levels, and on the risk of arterial thrombosis. Genetic variations in other regulators of VWF, including the ABO blood group, ADAMTS‐13, thrombospondin‐1 and the recently identified SNARE protein genes, have also been investigated. In this article, we review the current literature as exploring the associations between genetic variations and the risk of arterial thrombosis may help elucidate the role of VWF in the pathogenesis of arterial thrombosis. However, as studies frequently differ in design, population and endpoint, and are often underpowered, it remains unclear whether VWF is causally related to the occurrence of arterial thrombosis or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent arterial thrombosis. Nevertheless, current studies provide interesting results that do not exclude the possibility of VWF as causal mediator and justify further research into the relationship between VWF and arterial thrombosis. Large prospective studies are required to further establish the role of VWF in the occurrence of arterial thrombosis.     

The −589C>T polymorphism in the interleukin‐4 gene (IL‐4) is associated with a reduced risk of myocardial infarction in young individuals

Summary. Background: Inflammatory reactions contribute to the development of arterial disease. We investigated the role of interleukin‐4 (IL‐4) in the development of myocardial infarction (MI) by genotyping patients with MI and control subjects for the ?589C>T (rs2243250) single nucleotide polymorphism (SNP), which tags a functional haplotype of IL‐4. Methods and results: Study of Myocardial Infarctions Leiden (SMILE) included 560 men with a first MI and 646 control subjects. The Valencia study included 305 patients with MI at ≤52 years (men and women) and 310 control subjects. In SMILE no clear overall association with the ?589C>T genotype was found [odds ratio (OR) 0.84; 95% CI 0.37–1.95 for ?589TT and 0.82; 95% CI 0.62–1.07 for ?589CT compared with ?589CC]. In patients younger than 50 years, carriership of one or two ?589T alleles was associated with a reduced risk of MI (OR 0.57: 95% CI 0.34–0.95). This result was replicated in the Valencia study, where carriers of one or two ?589T alleles had a reduced risk of MI (OR 0.67: 95% CI 0.47–0.95), with a strong protective effect of the ?598T allele in homozygous ?589T (OR 0.33: 95% CI 0.10–1.05). In the control subjects of the Valencia study, the ?589T allele was associated with reduced levels of F1+2. Conclusion: Our data indicate that the IL‐4 haplotype tagged by the ?589T allele reduces the risk of MI in young individuals.     

Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromsø Study

Summary. Background: Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis. Objective: To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population. Patients/methods: OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromsø Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow‐up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI). Results: There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of follow‐up. Serum OPG (per SD [1.13 ng mL^?1] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11–1.31), ischemic stroke (1.32; 1.18–1.47), total mortality (1.34; 1.26–1.42), death because of ischemic heart disease, (1.35; 1.18–1.54), stroke (1.44; 1.19–1.75) and non‐vascular causes (1.31; 1.22–1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C‐reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73–1.43). Conclusions: Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non‐vascular causes independent of traditional cardiovascular risk factors.     

High blood hemoglobin concentration as risk factor of major atherosclerotic cardiovascular events in 114,159 healthy men and women in the Apolipoprotein MOrtality RISk study (AMORIS)

Abstract

Background. Few studies have tested differences in relationships between hemoglobin (Hb) and long-term risk of major cardiovascular diseases according to age and gender in healthy subjects as opposed to anemia.

Aims. Such relationships were examined and risk-tested in relation to Hb values in the Apolipoprotein MOrtality RISk (AMORIS) Study.

Methods. Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 114,159 subjects with mean follow-up of 11.8 years, the association between Hb and risk of acute myocardial infarction (AMI), ischemic stroke (IS), and congestive heart failure (CHF) by Cox regression analysis according to age and gender was studied.

Results. Elevated Hb levels were associated to acute myocardial infarction (AMI) (HR 1.10 (1.06–1.13) per SD change), mostly confined to men and younger subjects but with greater sex similarity trends for CHF. Slightly increased risks were seen for the lowest Hb levels in the elderly and in females. IS risk was positively and more linearly associated to Hb.

Interpretation. In AMORIS the highest AMI and CHF risks were found in the upper region of the distribution, but different shapes of relationships according to age and gender were found. IS associated positively with Hb. Key words:     

Insulin resistance and risk of venous thromboembolism: results of a population‐based cohort study

Summary. Background: Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity. Objective: We aimed to investigate whether insulin resistance is a risk factor for VTE. Methods: For this analysis we used the PREVEND prospective community‐based observational cohort study. Insulin resistance was measured as HOMA‐IR (homeostasis model assessment of insulin resistance) and fasting insulin. VTE was assessed using databases of the national registries of hospital discharge diagnoses, death certificates and the regional anticoagulation clinic. Results: Out of 7393 subjects, 114 developed VTE during a median follow‐up of 10.5 years. High HOMA‐IR was associated with increased risk of VTE after adjustment for traditional cardiovascular risk factors, CRP and markers of endothelial dysfunction (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.09–1.75; P = 0.007). When body mass index (BMI) was added to the model, BMI was a strong risk predictor for VTE (HR, 1.53; 95% CI, 1.24–1.88; P < 0.001) whereas HOMA‐IR no longer showed such an association (HR, 1.11; 95% CI, 0.85–1.43; P = 0.45). Results were similar for fasting insulin. Conclusion: Our population‐based cohort study shows an increased risk of VTE in subjects with increasing insulin resistance but not independently of BMI.     

The minor allele of GP6 T13254C is associated with decreased platelet activation and a reduced risk of recurrent cardiovascular events and mortality: results from the SMILE–Platelets project

Summary. Background: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. Methods: We performed a population‐based case–control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non‐fatal MI and unstable angina) and mortality (median follow‐up of 12 years). P‐selectin expression by platelets induced by crosslinked collagen‐related peptide (CRP‐XL) was measured by whole blood flow cytometry in 274 MI patients. Results: T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per‐allele hazard ratio 0.77, 95% confidence interval (CI) 0.56–1.06] and mortality (hazard ratio 0.57, 95% CI 0.37–0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66–0.99) and 0.73 (95% CI 0.55–0.96). The minor C‐allele was also strongly associated with a reduced percentage of P‐selectin‐expressing platelets. The reduction per C‐allele was 23% (95% CI 18–28%). In an independent study of 219 healthy volunteers, the per‐allele reduction of CRP‐XL‐induced aggregation was 10% (95% CI 2–18%). Conclusion: The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI.     

Protein S gene mutation c.946C > T (p.R316C) contributed to ischemic stroke in a man with von Willebrand disease type 3 caused by two novel VWF gene mutations,c.2328delT (p.A778Lfs* 23) and c.6521G > T (p.C2174F)

The risk factors for a family with VWD presenting with an ischemic stroke (IS) were explored. FVIII activity (FVIII:C), VWF antigen (VWF:Ag), and protein S activity were measured. Next generation sequencing (NGS) was performed targeting F8, F9, VWF, PROC, and PROS1. Sanger sequencing validation was performed on family members. The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL). NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister. Another VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in all members studied. A PROS1 mutation, c.946C > T (p.R316C), previously reported to relate to ischemic stroke, was found heterozygous in the patient, his father, and his daughter. Only the proband and daughter have a slightly decreased plasma protein S level. This may be the first case with type 3 VWD with severe VWF/FVIII deficiency presented with ischemic stroke contributed to by a protein S defect.     

Prospective study of circulating soluble CD40 ligand concentrations and the incidence of cardiovascular disease in a nested prospective case–control study of older men and women

Summary. Background: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation. Objectives: We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. Methods: Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, ‘nested’ in prospective UK studies of 4252 men and 4286 women aged 60–79 years, sampled from general practices in Britain in 1998–2000, with 7‐year follow‐up for fatal and non‐fatal MI and stroke. Results: sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL^?1 vs. 5.82 ng mL^?1; P = 0.5) or between stroke cases and controls (5.61 ng mL^?1 vs. 5.28 ng mL^?1, P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age‐adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors. Conclusions: sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.     

Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23 796 consecutive autopsies

BACKGROUND: The relationship between atherothrombotic disease and venous thromboembolism (VTE) remains unclear. PATIENTS AND METHODS: In a cohort of 23,796 consecutive autopsies, performed using a standardized procedure and representing 84% of all in-hospital deaths between 1970 and 1982 in an urban Swedish population, we investigated the relationship between verified arterial thrombosis and VTE, with the hypothesis that patients with thrombosis in major artery segments have increased odds of VTE. RESULTS: We found an increased risk of VTE in patients with arterial thrombosis (Odds ratio; OR adjusted for gender and age 1.4, 95% confidence interval; CI 1.3-1.5) (P < 0.001). Patients with cervico-cranial and peripheral artery thrombosis had an excess risk even when controlling for age and major concomitant diseases. A negative association between coronary thrombosis and VTE in the univariate analysis (OR 0.7; 95% CI 0.6-0.8) (P < 0.001), was less pronounced in the multivariate analysis (OR 0.8; 95% CI 0.7-1.0) (P = 0.016). CONCLUSIONS: A positive association between atherothrombosis and VTE was confirmed, except in patients with coronary thrombosis, where IHD as competing death cause is a possible confounder. Our findings indicate a potential for directed prevention, but may also imply similarities in etiology.