Data from national health registers as endpoints for the Tromsø Study: Correctness and completeness of stroke diagnoses.

AIM: To assess whether stroke diagnoses in national health registers are sufficiently correct and complete to replace manual collection of endpoint data for the Tromsø Study, a population-based epidemiological study. METHOD: Using the Tromsø Study Cardiovascular Disease Register for 2013-2014 as the gold standard, we calculated correctness (defined as positive predictive value, PPV) and completeness (defined as sensitivity) of stroke cases in four different data subsets derived from the Norwegian Patient Register and the Norwegian Stroke Register. We calculated the sensitivity and PPV with 95% confidence intervals (CIs) assuming a normal approximation of the binomial distribution. RESULTS: In the Norwegian Stroke Register we found a sensitivity of 79.8% (95% CI 74.2-85.4) and a PPV of 97.5% (95% CI 95.1-99.9). In the Norwegian Patient Register the sensitivity was 86.4% (95% CI 81.6-91.1) and the PPV was 84.2% (95% CI 79.2-89.2). The overall highest levels were found in a subset based on a linkage between the Norwegian Stroke Register and the Norwegian Patient Register, with a sensitivity of 88.9% (95% CI 84.5-93.3), and a PPV of 89.3% (95% CI 85.0-93.6). CONCLUSIONS: Data from the Norwegian Patient Register and from the linked data set between the Norwegian Patient Register and the Norwegian Stroke Register had acceptable levels of correctness and completeness to be considered as endpoint sources for the Tromsø Study Cardiovascular Disease Register. The benefits of using data from national registers as endpoints in epidemiological studies must be weighed against the impact of potentially decreased data quality.

Physical activity, resting heart rate, and atrial fibrillation: the Tromsø Study.

AIMS: The objective was to examine the association of physical activity and resting heart rate (RHR) with hospital-diagnosed atrial fibrillation (AF) in a Norwegian cohort. METHODS AND RESULTS: This prospective study included 20 484 adults (50.3% men) who participated in the third Tromsø Study survey in 1986-87. At baseline, physical activity was assessed by a validated questionnaire, and RHR was objectively measured. Participants were followed from baseline through 2010 with respect to incident cases of hospital-diagnosed AF documented on an electrocardiogram. During a mean follow-up period of 20 years (409 045 person-years), 750 participants (70.5% men) were diagnosed with AF. Compared with the low physical activity group, moderately active individuals had a 19% lower risk of any AF [adjusted hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.68-0.97], whereas highly active had similar risk of AF. Vigorously active individuals showed a non-significantly higher risk of AF (adjusted HR 1.37, 95% CI 0.77-2.43). Risk of AF increased with decreasing RHR (adjusted HR 0.92, 95% CI 0.86-0.98 for each 10 b.p.m. increase in RHR), and RHR < 50 b.p.m. was a risk factor for AF (P < 0.05). CONCLUSION: In this prospective cohort study, leisure time physical activity was associated with AF in a J-shaped pattern. Moderate physical activity was associated with a reduced risk of AF, whereas higher activity levels attenuated the benefits of moderate activity. Low RHR was a risk factor for AF. Our results support the hypothesis that moderate and vigorous physical activity may affect AF risk via different pathophysiological mechanisms.

Uric acid is associated with future atrial fibrillation: an 11-year follow-up of 6308 men and women--the Tromso Study.

AIMS: Serum uric acid (SUA) has been associated with cardiovascular disease in population studies, but its relation to atrial fibrillation (AF) is largely unknown. The aim of this study was to investigate the association between baseline SUA and future AF in a large population-based cohort. METHODS AND RESULTS: A total of 6308 men and women from a population survey in Tromsø, Norway in 1994-95 were followed-up for 10.8 years. The mean age at baseline was 60 years. Information on angina, myocardial infarction, diabetes, anti-hypertensive and diuretic treatment, physical activity, smoking and alcohol, and measurements of height, weight, blood pressure, SUA, total cholesterol, and high density lipoprotein-cholesterol were obtained at baseline. The outcome measure was first-ever AF, documented on an electrocardiogram. We identified 572 cases of incident AF. In multivariable Cox proportional hazards regression analysis adjusted for cardiovascular risk factors and concomitant diseases, SUA was associated with AF in both sexes. Hazard ratio per 1 SD increase in SUA (91 µmol/L) was 1.40 [95% confidence intervals (CI), 1.14-1.72] in women and 1.17 (95% CI, 1.02-1.36) in men. The upper quartile of SUA conferred a 76% increased risk for AF in women and 49% in men as compared with the lowest quartile. CONCLUSION: This prospective population-based cohort study showed that baseline SUA was associated with an increased risk for future AF in both sexes.

Validating Acute Myocardial Infarction Diagnoses in National Health Registers for Use as Endpoint in Research: The Tromsø Study.

PURPOSE: To assess whether acute myocardial infarction (MI) diagnoses in national health registers are sufficiently correct and complete to replace manual collection of endpoint data for a population-based, epidemiological study. PATIENTS AND METHODS: Using the Tromsø Study Cardiovascular Disease Register for 2013-2014 as gold standard, we calculated correctness (defined as positive predictive value (PPV)) and completeness (defined as sensitivity) of MI cases in the Norwegian Myocardial Infarction Register and the Norwegian Patient Register separately and in combination. We calculated the sensitivity and PPV with 95% confidence intervals using the Clopper-Pearson Exact test. RESULTS: We identified 153 MI cases in the gold standard. In the Norwegian Myocardial Infarction Register, we found a PPV of 97.1% (95% confidence interval (CI) 92.8-99.2) and a sensitivity of 88.2% (95% CI 82.0-92.9). In the Norwegian Patient Register, the PPV was 96.3% (95% CI 91.6-98.8) and the sensitivity was 85.6% (95% CI 79.0-90.8). The combined dataset of the Norwegian Myocardial Infarction Register and the Norwegian Patient Register had a PPV of 96.6% (95% CI 92.1-98.9) and a sensitivity of 91.5% (95% CI 85.9-95.4). CONCLUSION: MI diagnoses in both the Norwegian Myocardial Infarction Register and the Norwegian Patient Register were highly correct and complete, and each of the registers could be considered as endpoint sources for the Tromsø Study. A combination of the two national registers seemed, however, to represent the most comprehensive data source overall. The benefits of using data from national registers as endpoints in epidemiological studies include faster, less resource-intensive access to nationwide data and considerably lower loss to follow-up, compared to manual data collection in a limited geographical area.

Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment.

OBJECTIVE: Our objective was to examine the relation between neuropsychological function and subclinical hypothyroidism (SHT), defined as serum TSH of 3.5-10.0 mIU/liter and normal serum free T4 and free T3 levels, and to study the effect of T4 supplementation. SUBJECTS: A total of 89 subjects (45 males) with SHT and 154 control subjects (72 males) were recruited from a general health survey (the fifth Tromsø study). Sixty-nine of those with SHT were included in a placebo-controlled, double-blind intervention study with T4 medication for 1 yr. MAIN OUTCOME MEASURES: We used fourteen tests of cognitive function, Beck Depression Inventory, General Health Questionnaire, and a questionnaire on hypothyroid symptoms. RESULTS: The mean +/- sd serum TSH in the SHT and control group were 5.57 +/- 1.68 and 1.79 +/- 0.69 mIU/liter, respectively. There were no significant differences in cognitive function and hypothyroid symptoms between the two groups, but those with SHT scored significantly better than the controls on the GHQ-30. At the end of the intervention study, serum TSH in the T4 group (n = 36) and the placebo group (n = 33) were 1.52 +/- 1.51 and 5.42 +/- 1.96 mIU/liter, respectively. T4 substitution had no effect on any of the parameters measured. CONCLUSION: In subjects with SHT where the serum TSH level is in the 3.5-10.0 mIU/liter range, there is no neuropsychological dysfunction, and compared with healthy controls, there is no difference in symptoms related to hypothyroidism.

CHA2DS2-VASc score, left atrial size and atrial fibrillation as stroke risk factors in the Tromsø Study.

OBJECTIVE: CHA2DS2-VASc score, left atrial (LA) size and atrial fibrillation (AF) have individually been associated with stroke risk. Our aim was to investigate the predictive ability of combinations of these factors for the odds of incident stroke in a population-based cohort study. METHODS: We followed 2844 participants from the Tromsø Study from 1994 to 2012. Information on LA size and CHA2DS2-VASc score (age, sex, congestive heart failure, hypertension, vascular disease, stroke and diabetes) were obtained at baseline. AF status was recorded from medical records. The outcome measure was all strokes. The association between covariates and stroke was investigated by means of multivariate logistic regression analysis. RESULTS: A total of 325 participants (45% women, mean age at baseline 59.3 years) had a stroke. Incidence rates for stroke were 6.4 in women and 8.4 in men per 1000 person-years. Participants with CHA2DS2-VASc ≥1 and LA size <2.8 had ∼4 times (95% CI 2.6 to 5.3) increased odds of stroke, whereas participants with CHA2DS2-VASc ≥1 and LA size ≥2.8 had ∼9 times (95% CI 5.3 to 16.4) increased odds of stroke, compared with participants with CHA2DS2-VASc score 0, irrespective of AF status. Adjustment for significant covariates had minimal impact on the OR estimates. CONCLUSIONS: Combining CHA2DS2-VASc score ≥1 and enlarged LA size identified participants with high odds of stroke regardless of AF status.

Association between diastolic dysfunction and future atrial fibrillation in the Tromsø Study from 1994 to 2010.

OBJECTIVE: To investigate the association between echocardiographic measurements with emphasis on diastolic dysfunction and risk of atrial fibrillation (AF) in a population-based cohort study. METHODS: We followed 2406 participants from the Tromsø Study from 1994 to 2010. Left atrial (LA) size and mitral Doppler indices as measured by echocardiography were used for evaluating diastolic dysfunction. Information concerning age, systolic blood pressure, height, heart rate, body mass index, total and high-density lipoprotein cholesterol, self-reported use of alcohol, smoking, coffee, physical activity, antihypertensive treatment, prevalent coronary heart disease, valvular heart disease, heart failure, hypertrophy, diabetes and palpitations were obtained at baseline. The outcome measure was clinical AF, documented by an ECG. RESULTS: AF was detected in 462 subjects (193 women). Mean age at baseline was 62.6 years. Incidence rate of clinical AF was 12.6 per 1000 person-years. In multivariable Cox proportional hazards regression analysis, moderately enlarged LA was associated with 60% (95% CI 1.2 to 2.0) increased risk of AF. Severely enlarged LA had HR for AF of 4.2 (95% CI 2.7 to 6.5) with p value for linear trend <0.001, and the association was similar in both sexes. Abnormal mitral Doppler flow adjusted for predictor variables did not show a statistically significant association with AF risk. However, when LA size was also adjusted for, the risk of AF increased by 30% (95% CI 1.0 to 1.6). CONCLUSIONS: Our findings suggest that enlarged LA as a measure for diastolic dysfunction is a significant risk factor for AF in both sexes, and adding measures of abnormal diastolic flow increased the predictive ability significantly.

Palpitations are predictive of future atrial fibrillation. An 11-year follow-up of 22,815 men and women: the Tromsø Study.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia which increases morbidity and mortality. Identification of risk factors is therefore important. We examined the impact of palpitations and cardiovascular risk factors in prediction of AF (all types) and lone AF in a large population-based cohort. DESIGN: We carried out a prospective population-based cohort study. METHODS: A total of 22,815 participants from a population survey in 1994-1995 were followed-up for a mean of 11.1 years. Mean age at baseline was 46 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol and high-density lipoprotein (HDL)-cholesterol, and information on palpitations, diabetes, angina, myocardial infarction, and antihypertensive treatment were obtained at baseline. The outcome measure was first-ever AF, documented on an electrocardiogram. Cox proportional hazards regression model was used to estimate hazard ratios (HRs) for AF. RESULTS: Palpitations were associated with increased risk of AF in both women (HR 1.62, 95% confidence interval [CI] 1.29-2.02) and men (HR 1.91, 95% CI 1.54-2.35). For hypertension the HR for AF was 1.98 (1.46-2.69) in women and 1.40 (1.13-1.74) in men. The HR for 1 SD increase in body mass index (BMI) was 1.16 (1.06-1.27) in women and 1.47 (1.32-1.63) in men. Body height and BMI were associated with increased risk for lone AF in men. CONCLUSION: Palpitations, hypertension and BMI were predictive of future atrial fibrillation in both sexes.

Inflammatory biomarkers as risk factors for future atrial fibrillation. An eleven-year follow-up of 6315 men and women: the Tromsø study.

BACKGROUND: Inflammatory biomarkers are reported as risk factors for atrial fibrillation (AF), but their impact is uncertain. OBJECTIVE: We investigated the associations between inflammatory biomarkers and future AF in a large general cohort. METHODS: Available markers were white blood cells (WBCs) with subgroups, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and osteoprotegerin (OPG). A total of 6315 men and women from a population survey in Tromsø, Norway in 1994 to 1995 were followed for a mean of 10.9 years. Mean age at baseline was 60 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, WBC count, and information on diabetes, angina, myocardial infarction, and antihypertensive treatment, were obtained at baseline. Fibrinogen, hs-CRP, and OPG were obtained at a follow-up visit. The outcome measure was first-ever AF, documented on an electrocardiogram. The Cox proportional hazards regression model was used to estimate hazard ratios of AF. RESULTS: In the multivariable analysis, adjusted for traditional cardiovascular risk factors and other inflammatory biomarkers, hs-CRP was associated with AF in men only (hazard ratio = 1.14 for a 1 SD increase; 95% CI, 1.02-1.28). There was a significant increase in AF across quartiles of WBCs in men (P = 0.007) and in the total study population (P = 0.004). OPG was associated with AF in patients free of coronary heart disease at baseline. Fibrinogen and subgroups of WBCs showed no significant association with AF. CONCLUSION: This population-based cohort study showed that hs-CRP was independently associated with AF in men, but apparently not in women, and that patients with WBCs in the upper quartile had increased risk of AF.

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.