Erin Mathiesen Hald

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 × 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.

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 ∼10,000 individuals and followed up the top signals in an additional ∼10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 × 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 × 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.

Competing Risk of Atherosclerotic Risk Factors for Arterial and Venous Thrombosis in a General Population: The Tromsø 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/m2 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. Conclusion—Our findings imply that traditional atherosclerotic risk factors, such as smoking, hypertension, dyslipidemia, and diabetes mellitus are not shared by arterial and venous thrombosis.

Venous Thromboembolism Increases the Risk of Atrial Fibrillation: The Tromsø 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.

Atrial fibrillation and future risk of venous thromboembolism:the Tromsø study

Whether atrial fibrillation is related to risk of venous thromboembolism (VTE) has not been extensively studied. Therefore, we investigated the association between atrial fibrillation and future risk of VTE in a population‐based cohort.

Carotid Atherosclerosis Predicts Future Myocardial Infarction But Not Venous Thromboembolism

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.

Carotid Atherosclerosis Predicts Future Myocardial Infarction But Not Venous Thromboembolism The Tromsø 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.

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

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.

Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromsø Study

Essentials Registry‐based studies indicate a link between arterial‐ and venous thromboembolism (VTE). We studied this association in a cohort with confounder information and validated outcomes. Myocardial infarction (MI) was associated with a 4.8‐fold increased short‐term risk of VTE. MI was associated with a transient increased risk of VTE, and pulmonary embolism in particular.