Red Cell Distribution Width and Risk of Atrial Fibrillation and Subsequent Thromboembolism: The Tromsø Study.

Introduction Red cell distribution width (RDW) is associated with cardiovascular diseases, including atrial fibrillation (AF) and venous thromboembolism (VTE). Whether RDW is a risk marker for thromboembolic events in AF patients is scarcely known. We aimed to assess the association between RDW and the risk of AF, and AF-related VTE and ischemic stroke, in a population-based cohort. Methods We measured RDW in 26,111 participants from the Tromsø Study (1994-1995), and registered incident AF cases through December 31, 2013. Among participants with AF, first-ever VTEs and ischemic strokes were registered from the date of AF diagnosis through the end of follow-up. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for AF by quartiles of RDW. Furthermore, we calculated cause-specific HRs for VTE and ischemic stroke by tertiles of RDW for participants with AF. Results There were 2,081 incident AF cases during a median of 18.8 years of follow-up. Subjects with RDW in the highest quartile (RDW ≥ 13.3%) had 30% higher risk of AF than those in the lowest quartile (RDW ≤ 12.3%). Among those with AF, subjects with RDW in the upper tertile had a doubled risk of ischemic stroke (HR 2.07, 95% CI 1.20-3.57). In contrast, RDW was not associated with incident VTE in subjects with AF. Conclusion RDW was significantly associated with incident AF in a general population. Among subjects with AF, high RDW was associated with ischemic stroke, but not VTE.

Atrial Fibrillation and Cause-Specific Risks of Pulmonary Embolism and Ischemic Stroke.

BACKGROUND: Atrial fibrillation (AF) is a well-established risk factor for ischemic stroke (IS). Emerging evidence also indicates an association between AF and pulmonary embolism (PE). Because IS may potentially mediate the observed risk of PE in AF, we aimed to assess the impact of AF on the cause-specific risks of PE and IS in a large cohort recruited from the general population. METHODS AND RESULTS: We observed 29 842 participants from 3 surveys of the Tromsø study (inclusion in 1994-1995, 2001-2002, and 2007-2008) to the end of 2012. Incident events of AF, IS, and PE during follow-up were recorded, and information on potential confounders was obtained at baseline. Cox regression models, with AF as a time-dependent variable, were used to calculate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for PE and IS. There were 2067 participants diagnosed as having AF, 296 with PE and 1164 with IS, during a median of 17.6 years of follow-up. The risks of PE (HR, 10.88; 95% CI, 6.23-18.89) and IS (HR, 6.16; 95% CI, 4.47-8.48) were substantially increased during the first 6 months after AF diagnosis, with crude incidence rates of 18.5 per 1000 person-years for PE and 52.8 per 1000 person-years for IS. The risk estimates remained elevated for both PE (HR, 1.72; 95% CI, 1.10-2.71) and IS (HR, 2.45; 95% CI, 2.05-2.92) throughout the study period. CONCLUSIONS: AF was associated with increased cause-specific risks of both PE and IS. Our findings infer that the risk of PE in AF is not explained by intermediate IS.

Myocardial infarction and future risk of cancer in the general population-the Tromsø Study.

The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n = 28,763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariable-adjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21-1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29-3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27-2.03) higher HR of future cancer more than 3 years after the event. The increased IRs were higher in women than men. Patients with MI had a higher short- and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.

Ischemic Stroke and Risk of Venous Thromboembolism in the General Population: The Tromsø Study.

BACKGROUND: Even though clinical data support a relation between ischemic stroke and venous thromboembolism (VTE), the strength and time dependence of the association remain to be settled at the population level. We therefore aimed to investigate the association between ischemic stroke and VTE in a prospective population-based cohort. METHODS AND RESULTS: Participants (n=30 002) were recruited from 3 surveys of the Tromsø study (conducted in 1994-1995, 2001, and 2007-2008) and followed through 2010. All incident events of ischemic stroke and VTE during follow-up were recorded. Cox-regression models with age as time scale and ischemic stroke as a time-dependent variable were used to calculate hazard ratios (HR) of VTE adjusted for cardiovascular risk factors. During a median follow-up time of 15.7 years, 1360 participants developed ischemic stroke and 722 had a VTE. The risk of VTE was highest the first month (HR 19.7; 95% CI, 10.1-38.5) and from 1 to 3 months after the stroke (HR 10.6; 95% CI 5.0-22.5), but declined rapidly thereafter. The risk estimates were approximately the same for deep vein thrombosis (HR 19.1; 95% CI, 7.8-38.5), and pulmonary embolism (HR 20.2; 95% CI, 7.4-55.1). Stroke was associated with higher risk for provoked (HR 22.6; 95% CI, 12.5-40.9) than unprovoked VTE (HR 7.4; 95% CI, 2.7-20.1) the first 3 months. CONCLUSIONS: The risk of VTE increased during the first 3 months after an ischemic stroke. The particularly high risk of provoked VTE suggests that additional predisposing factors, such as immobilization, potentiate the VTE risk in patients with ischemic stroke.

Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study.

BACKGROUND: Pulmonary embolism (PE) may trigger atrial fibrillation through increased right atrial pressure and subsequent atrial strain, but the degree of evidence is low. In this study, we wanted to investigate the impact of incident venous thromboembolism (VTE) on future risk of atrial fibrillation in a prospective population-based study. METHODS AND RESULTS: The study included 29 974 subjects recruited from the Tromsø study (1994-1995, 2001-2002, 2007-2008). Incident VTE and atrial fibrillation events were registered from date of enrolment to end of follow-up, December 31, 2010. Cox proportional hazard regression models using age as time-scale and VTE as a time-dependent variable were used to estimate crude and multivariable hazard ratios (HRs) for atrial fibrillation with 95% confidence intervals (CIs). During 16 years of follow up, 540 (1.8%) subjects had an incident VTE event, and 1662 (5.54%) were diagnosed with atrial fibrillation. Among those with VTE, 50 (9.3%) developed subsequent atrial fibrillation. Patients with VTE had 63% higher risk of atrial fibrillation compared to subjects without VTE (multivariable-adjusted HR: 1.63, 95% CI: 1.22 to 2.17). The risk of atrial fibrillation was particularly high during the first 6 months after the VTE event (HR 4.00, 95% CI: 2.21 to 7.25) and among those with PE (HR 1.78, 95% CI: 1.13 to 2.80). CONCLUSIONS: We found that incident VTE was associated with future risk of atrial fibrillation. Our findings support the hypothesis that PE may lead to cardiac dysfunctions that, in turn, could trigger atrial fibrillation.

Carotid atherosclerosis predicts future myocardial infarction but not venous thromboembolism: the Tromso study.

OBJECTIVE: Recent studies have suggested that arterial and venous thrombosis share common risk factors. Although carotid atherosclerosis is associated with arterial cardiovascular events, its role in venous thromboembolic disease is unclear. We wanted to investigate and compare the effect of carotid atherosclerosis on the risk of myocardial infarction (MI) and venous thromboembolism (VTE) in a general population, taking into account competing risks. APPROACH AND RESULTS: Mean intima-media thickness and total plaque area in the right carotid artery were measured with ultrasound in 6257 people aged 25 to 84 years who participated in a population-based health study, the Tromsø Study, from 1994 to 1995. Incident MI and VTE events were registered from date of enrollment to end of follow-up on December 31, 2010. Cox proportional hazards regression models using age as time scale were used to estimate cause-specific hazard ratios with 95% confidence intervals for MI and VTE by increasing levels of intima-media thickness and total plaque area. There were 894 incident MI cases and 256 VTE events during a median of 15.4 years of follow-up. The risk of MI increased significantly across quartiles of mean intima-media thickness (P for trend <0.001) and with increasing total plaque area (P for trend <0.001), but neither intima-media thickness (P for trend=0.94) nor total plaque area (P for trend=0.45) was associated with VTE risk in multivariable-adjusted analysis. CONCLUSIONS: In this study, carotid atherosclerosis was strongly associated with future MI but not with VTE. Our findings suggest that carotid atherosclerosis does not represent a link between arterial and venous thrombosis.

Postprandial lipemia is not increased in patients with previous unprovoked venous thromboembolism.

BACKGROUND: Patients with arterial cardiovascular disease have increased postprandial lipemia, and plasma levels of postprandial remnants are related to the progression of atherosclerosis. Studies have shown that patients with unprovoked venous thromboembolism have increased risk of arterial cardiovascular disease. OBJECTIVE: To investigate whether patients with a history of unprovoked venous thromboembolism have increased postprandial lipemia. METHODS: A population-based case-control study was performed in 20 patients with a history of unprovoked venous thromboembolism and 20 age- and gender-matched healthy controls. Participants were subjected to a standard fat tolerance test (1 g/kilo body weight) with subsequent blood sampling every second hour for 8 hours. Lipids were measured by traditional methods and lipoprotein subclasses by proton nuclear magnetic resonance. RESULTS: Fasting lipids and lipoprotein subclasses did not differ between groups. The postprandial lipemia, assessed by the incremental area under the triglyceride curve, was not different in venous thromboembolism patients and healthy controls (5.0 ± 3.6 mmol/L∗h vs 5.3 ± 4.4 mmol/L∗h, P = .81). Similarly, the distribution and size of the lipoprotein subclasses obtained 4 hours postprandially did not differ between groups. CONCLUSION: Patients with a history of unprovoked venous thromboembolism had similar lipoprotein subclasses size, distribution, and postprandial lipemia as healthy controls. Our findings indicate that postprandial lipemia is not a link between unprovoked venous thromboembolism and arterial cardiovascular disease.

Competing risk of atherosclerotic risk factors for arterial and venous thrombosis in a general population: the Tromso study.

OBJECTIVE: To investigate and compare the impact of traditional atherosclerotic risk factors for the risk of arterial and venous thrombosis, taking into account competing risks. METHODS AND RESULTS: In 1994-1995, 26,185 subjects were screened in the Tromsø study. Information on traditional atherosclerotic risk factors was obtained by physical examination, blood samples, and questionnaires. Subjects were followed to the first incident event of myocardial infarction (MI) or venous thromboembolism (VTE), or December 31, 2005. During a median of 10.8 years of follow-up, there were 1279 cases of incident MI and 341 VTE events. Advancing age and high body mass index were both associated with MI and VTE. Hazard ratio per decade of age was 2.34 (95% CI: 2.25-2.43) for MI and 1.87 (1.74-2.01) for VTE, and 3 kg/m(2) increase in body mass index was associated with 1.16 (1.11-1.21) and 1.20 (1.12-1.29) increased risk of MI and VTE, respectively. Blood pressure, high levels of triglycerides and total cholesterol, low HDL cholesterol, self-reported diabetes, and smoking were all associated with increased risk of MI but not associated with VTE. CONCLUSIONS: Our findings imply that traditional atherosclerotic risk factors, such as smoking, hypertension, dyslipidemia, and diabetes mellitus are not shared by arterial and venous thrombosis.

High-sensitivity C-reactive protein is not a risk factor for venous thromboembolism: the Tromso study.

BACKGROUND: High-sensitivity C-reactive protein is associated with risk of arterial cardiovascular disease but conflicting results have been reported on its role in venous thromboembolic disease. The objective of our study was to investigate the association between high-sensitivity C-reactive protein levels and risk of future venous thromboembolism in a prospective cohort recruited from a general population. DESIGN AND METHODS: High-sensitivity C-reactive protein was measured in serum samples from 6,426 men and women, aged 25-84 years, recruited from the Tromsø Study in the period 1994-1995. Incident venous thromboembolism events (n=209) were registered during a median of 12.5 years of follow up. Cox's proportional hazards regression models were used to estimate age- and gender-and multivariable-adjusted hazard ratios with 95% confidence intervals for total venous thromboembolism, and for provoked and unprovoked venous thromboembolism by increasing levels of high-sensitivity C-reactive protein. RESULTS: There was no increased risk of venous thromboembolism per 1 standard deviation increase in high-sensitivity C-reactive protein (hazard ratio 1.08; 95% confidence interval 0.95-1.23) or across quartiles of high-sensitivity C-reactive protein (P for trend 0.6) in analyses adjusted for age and gender. Further adjustment for body mass index, smoking and diabetes did not alter the risk estimates. Moreover, high-sensitivity C-reactive protein was not associated with venous thromboembolism in either gender specific analysis or in separate analyses of provoked and unprovoked venous thromboembolism events. CONCLUSIONS: In this prospective study, serum levels of high-sensitivity C-reactive protein were not associated with future development of venous thromboembolism. Our findings do not suggest a causal role for C-reactive protein in the pathogenesis of venous thromboembolism.

Several common variants modulate heart rate, PR interval and QRS duration.

Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in approximately 10,000 individuals and followed up the top signals in an additional approximately 10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 x 10(-7)). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 x 10(-5) and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval.

A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke.

We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.