Increasing population height and risk of incident atrial fibrillation: the Copenhagen City Heart Study.

Aims: The incidence of atrial fibrillation (AF) has increased significantly over the last decades. Population height is changing in many countries. Height is an important risk factor for AF. The aim of the present study was to assess the role of changes in population height in the increased risk of AF. Methods and results: The Copenhagen City Heart Study comprises 18 852 randomly selected men and women aged 20-93 years, studied in four separate cross-sectional surveys in 1976-78, 1981-83, 1991-94, and 2001-03, including physical examination, electrocardiogram (ECG), and standard questionnaires. Hospitalization and mortality data were collected from public registers. Prevalent AF was determined from ECGs and incident AF from register diagnoses. During follow-up, age-standardized prevalence of AF increased significantly from 1.35% to 2.11% in men and from 0.67% to 1.07% in women (P < 0.001). Incident AF increased four-fold in both men and women [hazard ratio (HR) 4.16, 95% confidence interval (CI) 3.27-5.29; P < 0.001]. In multivariable Fine and Gray subdistribution hazards regression analyses, height was consistently an important risk factor for incident AF with HRs between 1.35 (95% CI 1.10-1.66; P = 0.004) and 1.65 (95% CI 1.40-1.93; P < 0.001). Population height increased with 3.3 cm for men and 2.1 cm for women, and population attributable risks for height was 20-30%. Conclusion: Height is a powerful risk factor for AF. Adult height is attained at age 20, while AF incidence occurs 50 years later. Given a causal relationship between height and AF incidence, increased population height in Denmark will contribute to an increase in AF occurrence for at least 25 more years.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Predictor of Incident Atrial Fibrillation.

Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic low-grade inflammation and a potent predictor of cardiovascular events. We hypothesized that plasma suPAR levels would predict new-onset atrial fibrillation (AF) in a large cohort of con-secutively admitted acute medical patients during long-term follow-up. In 14,764 acutely ad-mitted patients without prior or current AF, median suPAR measured upon admission was 2.7 ng/ml (interquartile range (IQR) 1.9-4.0). During a median follow-up of 392 days (IQR 218-577), 349 patients (2.4%) were diagnosed with incident AF. suPAR levels at admission significantly predicted subsequent incident AF (HR per doubling of suPAR: 1.21, 95% CI 1.05-1.41, adjusted for age and sex). After further adjustment for Charlson score, plasma C-reactive protein (CRP), plasma creatinine and blood hemoglobin-levels, the result remained essentially unaltered (HR per doubling of suPAR: 1.20, 95% CI: 1.01-1.42). In multivariate ROC curve analysis, combining age, sex, Charlson score, CRP, creatinine, and hemoglobin (AUC 0.77, 95% CI 0.75-0.79), the addition of suPAR did not improve the prediction of incident AF (AUC 0.77, 95% CI 0.75-0.79, P=0.89). Plasma suPAR is independently associated with subsequent new-onset AF in a population of recently hospitalized patients, but the addition of suPAR to baseline risk markers appears not to improve the prediction of AF.

Occupational physical activity, but not leisure-time physical activity increases the risk of atrial fibrillation: The Copenhagen City Heart Study.

BACKGROUND: Previous findings regarding physical activity and risk of incident atrial fibrillation (AF) are controversial, focusing on leisure-time physical activity (LTPA) and without distinguishing it from occupational physical activity (OPA). Our aim was to study the association between physical activity and risk of AF, with special attention to the possible divergent effects of OPA and LTPA. METHODS AND RESULTS: In a prospective, observational cohort study, 17,196 subjects were included from the Copenhagen Population Register. All participants had a physical examination, a 12-lead electrocardiogram (ECG), and answered a questionnaire regarding health and physical activity. Participants without previously diagnosed AF who answered adequately regarding OPA and LTPA were included. LTPA and OPA were each graded into four levels. Follow-up were carried out between 1981-1983, 1991-1994, and 2001-2003. Information regarding hospitalization and mortality was drawn from the National Patient Registry and the Registry of Causes of Death. Outcome was incident AF as determined by follow-up ECG or register diagnosis. In univariable Cox regression analysis all sub-groups of OPA had a significant higher risk of AF compared to moderate OPA. When adjusting for confounders, the risk remained significantly increased for high OPA (hazard ratio (HR) 1.21 (95% confidence interval (CI) 1.02-1.43), p = 0.028), and very high OPA (HR 1.39 (95% CI 1.03-1.88), p = 0.034). We found no significant association between LTPA and incident AF. CONCLUSIONS: High and very high OPA were associated with a significantly increased risk of incident AF. LTPA was not associated with risk of incident AF.

Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population.

OBJECTIVES: The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of atrial fibrillation is a robust and perhaps even causal association. BACKGROUND: Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation. METHODS: We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene polymorphisms and had high-sensitivity CRP levels measured. RESULTS: A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to 1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to 1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP polymorphisms associated with up to a 63% increase in plasma CRP levels (p < 0.001), but not with increased risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44]; p < 0.001). CONCLUSIONS: Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk.

Flow-mediated dilatation has no independent prognostic effect in patients with chest pain with or without ischaemic heart disease.

OBJECTIVE: The purpose of this study was to assess the prognostic effect of flow-mediated dilatation (FMD) in patients with chest pain admitted to a coronary care unit. METHODS: Endothelium-dependent FMD in the brachial artery was examined in 223 patients with acute chest pain. All patients underwent a stress test at the time of admittance. On the basis of a positive stress test, a prior myocardial infarction (MI), prior percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG), 137 patients were categorized as having ischaemic heart disease (IHD). RESULTS: Patients with IHD had significantly lower FMD than patients without IHD (p=0.002). During a mean follow-up of 4.2 years, 90 patients had an endpoint event, i.e. cardiovascular death, acute MI, unstable angina pectoris, PCI or CABG. In univariate analysis, FMD <3 % was associated with an increased hazard of the combined endpoint (p=0.04). In multivariate analysis, adjusted for age, gender, IHD and body mass index, no association between FMD and the combined endpoint was found (p=0.99). CONCLUSION: FMD is associated with IHD, but has no independent prognostic effect in patients with chest pain.

Atrial fibrillation pharmacotherapy after hospital discharge between 1995 and 2004: a shift towards beta-blockers.

AIMS: To study evolvement in pharmacotherapy of atrial fibrillation from 1995 to 2004. METHODS AND RESULTS: All Danish patients were discharged following first-time atrial fibrillation and their pharmacotherapy was identified by individual-level-linkage of nationwide registers of hospitalization and drug dispensing from pharmacies. A total of 108 791 patients survived 30 days after discharge and were included. In 1995-1996, 7.4% of the patients received beta-blockers, increasing to 44.3% in 2003-2004. The corresponding figures for amiodarone were 2.9 and 5.4%. In contrast, use of nondihydropyridine calcium-channel blockers, digoxin, sotalol, and class 1C antiarrhythmics decreased from 20.6, 63.9, 21.3, and 4.0% in 1995-1996 to 12.6, 43.8, 4.2, and 1.3% in 2003-2004, respectively. Notably, patients receiving anticoagulants increased from 29.8 to 43.5%. Multivariate logistic regression analysis revealed females to be associated with more use of digoxin, but less use of amiodarone and oral anticoagulants than males. Patients above 80 years received less pharmacotherapy, apart from digoxin treatment that was more commonly used in elderly. CONCLUSION: Pharmacotherapy of atrial fibrillation has changed towards increased beta-blocker use with a coincident decrease in the use of other rate-limiting drugs and sotalol. Treatment with amiodarone or class 1C antiarrhythmics remained very low. Oral anticoagulant therapy increased considerably, but women and elderly were apparently undertreated.

Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.

BACKGROUND: The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. We analyzed the risk of rehospitalization for acute myocardial infarction (MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with prior MI. METHODS AND RESULTS: All patients with first-time MI between 1995 and 2002 as well as all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. CONCLUSIONS: Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI and should therefore be used with particular caution in these patients.

Fibrinogen and albumin levels and risk of atrial fibrillation in men and women (the Copenhagen City Heart Study).

Cross-sectional and limited prospective evidence has suggested that inflammatory markers may predict for the risk of atrial fibrillation (AF). In a prospective cohort study, we studied the risk of incident AF among 8,870 women and men free of cardiovascular disease enrolled in the Copenhagen City Heart Study. We measured plasma fibrinogen and serum albumin levels at a study visit from 1991 to 1994. We identified 286 subsequent cases of AF during a mean of 7.5 years of follow-up by a validated nationwide registry of all hospitalizations. The fibrinogen levels at baseline were associated with a higher risk of AF, with a multivariate-adjusted hazard ratio for the highest versus lowest quartiles of 1.98 (95% confidence interval [CI] 0.94 to 4.17) among men and 2.14 (95% CI 1.15 to 3.96) among women. The albumin levels were inversely associated with the risk of AF among women (hazard ratio 0.47, 95% CI 0.28 to 0.77) but not among men (hazard ratio 1.01, 95% CI 0.56 to 1.84). Additional adjustment for cases of coronary heart disease, congestive heart failure, and stroke that occurred during follow-up did not attenuate these associations. In conclusion, higher levels of fibrinogen and lower levels of albumin were prospectively associated with a higher risk of AF, even accounting for their relation with the risk of cardiovascular disease. These findings support the hypothesis that inflammation contributes to the etiology of AF.

Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction.

AIMS: To study initiation, dosages, and compliance with beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors, and statins in patients after acute myocardial infarction (AMI) and to identify likely targets for improvement. METHODS AND RESULTS: Patients admitted with first AMI between 1995 and 2002 were identified by linking nationwide administrative registers. A total of 55 315 patients survived 30 days after discharge and were included; 58.3% received beta-blockers, 29.1% ACE-inhibitors, and 33.5% statins. After 1, 3, and 5 years, 78, 64, and 58% of survivors who had started therapy were still receiving beta-blockers, 86, 78, and 74% were receiving ACE-inhibitors, and 85, 80, and 82% were receiving statins, respectively. Increased age and female sex were associated with improved compliance. The dosages prescribed were generally 50% or less of the dosages used in clinical trials, and dosages did not increase during the observation period. Patients who did not start treatment shortly after discharge had a low probability of starting treatment later. CONCLUSION: The main problem with underuse of recommended treatment after AMI is that treatment is not initiated at an appropriate dosage shortly after AMI. A focused effort in the immediate post-infarction period would appear to provide long-term benefit.

Alcohol consumption and risk of atrial fibrillation in men and women: the Copenhagen City Heart Study.

BACKGROUND: The relationship of the full range of alcohol consumption with risk of incident atrial fibrillation has been inconsistent in previous, mainly case-control studies. METHODS AND RESULTS: In a prospective cohort study, we studied the association between self-reported alcohol use and incident atrial fibrillation among 16,415 women and men enrolled in the Copenhagen City Heart Study. We ascertained use of beer, wine, and spirits individually at up to 3 study visits with a structured questionnaire. We identified cases of atrial fibrillation by routine study ECGs and a validated nationwide registry of all hospitalizations. A total of 1071 cases occurred during follow-up. Among both women and men, alcohol consumption throughout the moderate range was not associated with risk of atrial fibrillation. However, consumption of 35 or more drinks per week among men was associated with a hazard ratio of 1.45 (95% CI 1.02 to 2.04); few women consumed this amount of alcohol. Approximately 5% of cases of atrial fibrillation among men were attributable to heavy alcohol use. Further adjustment for blood pressure and incident coronary heart disease and congestive heart failure did not attenuate the association (hazard ratio 1.63; 95% CI 1.15 to 2.31). CONCLUSIONS: Heavy alcohol consumption is associated with a higher risk of atrial fibrillation, at least among men. This relationship does not appear to be related to the adverse effects of heavy drinking on coronary heart disease or blood pressure.

Nationwide trends in the prescription of beta-blockers and angiotensin-converting enzyme inhibitors after myocardial infarction in Denmark, 1995-2002.

OBJECTIVES: To study the use of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) in Denmark from 1995 to 2002. DESIGN: Information about patients with first AMI aged > or = 30 years and the dispensing of beta-blockers and ACE inhibitors from pharmacies within 30 d from discharge was obtained from the National Patient Registry and the Danish Registry of Medicinal Product Statistics. RESULTS: Beta-blocker use increased from 38.1% of patients in 1995 to 67.9% in 2002 (OR = 3.85, CI: 3.58-4.13). Women, elderly patients and patients taking loop-diuretics and antidiabetic drugs received beta-blockers less frequently, but patients taking loop-diuretics or antidiabetic drugs had the greatest increase. ACE inhibitor use increased from 24.5 to 35.5% (OR = 1.86, CI: 1.72-2.01). Women, patients aged < 60 years or > or = 80 years and patients not taking loop-diuretics received ACE inhibitors less frequently, but patients not taking loop-diuretics had the greatest increase. CONCLUSIONS: Beta-blocker use increased markedly post-AMI from 1995 to 2002, whereas ACE inhibitor use increased modestly. The results suggested undertreatment of women, elderly patients and people with diabetes.

Statin use after acute myocardial infarction: a nationwide study in Denmark.

AIMS: To study outpatient statin use after first acute myocardial infarction (AMI) in Denmark between 1995 and 2002 and to determine the predictors of statin use. METHODS: This is a nationwide population-based study using administrative registries. Patients with first AMI between 1995 and 2002 older than 30 years of age and alive 6 months after discharge (n = 45 219) were identified through the National Patient Registry. The statins purchased by these patients within 6 months after discharge were determined using the Registry of Medicinal Product Statistics, a nationwide prescription database. RESULTS: Statin use following AMI increased from 13% in 1995 to 61% in 2002. In 2002, 81% of patients aged 30-64 years used statins. Older patients used fewer statins, but use increased more among patients aged 75-84 years: from 1.3% to 43%. Use in elderly patients did not differ according to gender in 2000-02, but young men used more than younger women. In 2000-02, patients with diabetes (odds ratio (OR): 0.84; 95% confidence interval (CI): 0.74-0.95) and with heart failure (OR: 0.70; 95% CI: 0.64-0.76) were undertreated; this trend was present throughout the period. CONCLUSIONS: In this nationwide study, younger patients after AMI had high statin use in 2002, but high-risk patients such as those with diabetes and heart failure were still being undertreated.

Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (The Copenhagen City Heart Study).

The Copenhagen City Heart Study is a population-based cohort study. Using baseline data from 3 cohort examinations (1976 to 1978, 1981 to 1983, and 1991 to 1994), we analyzed the gender-specific effect of atrial fibrillation (AF) on the risk of stroke and cardiovascular death during 5 years of follow-up. Baseline data from 29,310 subjects were included. AF was documented in 276 subjects (110 women and 166 men). During a mean follow-up of 4.7 years, 635 strokes were identified, 35 of which occurred in subjects who had AF (22 women and 13 men). After adjustment for age and co-morbidity, the effect of AF on the risk of stroke was 4.6-fold greater in women (hazard ratio 7.8, 95% confidence interval 5.8 to 14.3) than in men (hazard ratio 1.7, 95% confidence interval 1.0 to 3.0). Cardiovascular death occurred in 1,122 subjects, 63 of whom had AF (28 in women and 35 in men). The independent effect of AF on cardiovascular mortality rate was 2.5-fold greater in women (hazard ratio 4.4, 95% confidence interval 2.9 to 6.5) than in men (hazard ratio 2.2, 95% confidence interval 1.6 to 3.1). Our results indicate that AF is a much more pronounced risk factor for stroke and cardiovascular death in women than in men.

Sex-specific increase in the prevalence of atrial fibrillation (The Copenhagen City Heart Study).

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. It is a risk factor for stroke and premature death. We studied the temporal changes in the prevalence of AF from 1976 to 1994 in a random population aged 50 to 89 years. The prevalence of AF, diagnosed from electrocardiograms (ECGs), was determined in 8,606 patients examined in 1976 to 1978, in 8,943 patients examined in 1981 to 1983, and in 6,733 subjects examined in 1991 to 1994. Changes in prevalence of AF were estimated by logistic regression analysis. In men, the age-standardized prevalence of AF increased from 1.4% in 1976 to 1978 (odds ratio [OR] 1.0, reference) to 1.9% in 1981 to 1983 (OR 1.6, 95% confidence interval [CI] 1.1 to 2.1), and to 3.3% in 1991 to 1994 (OR 2.3, 95% CI 1.6 to 3.4, p<0.001, adjusted for age). In women, the prevalence of AF decreased from 1.5% in 1976 to 1978 (OR 1.0, reference) to 1.0% in 1981 to 1983 (OR 0.7, 95% CI 0.5 to 1.0), and to 1.1% in 1991 to 1994 (OR 0.7, 95% CI 0.5 to 1.0), although the overall decrease was not significant (p=0.11, adjusted for age). After adjusting for changes in comorbidity, body weight, and height, the increase in the prevalence of AF in men from 1976 to 1978 and from 1991 to 1994 remained significant (OR 1.9, 95% CI 1.3 to 2.8, p=0.002). Although unchanged in women, the prevalence of AF in men more than doubled from the 1970s to the 1990s. The factors responsible for this gender-specific increase in the prevalence of this common arrhythmia have yet to be identified.

Rising rates of hospital admissions for atrial fibrillation.

BACKGROUND: Atrial fibrillation is a common arrhythmia associated with excess morbidity and mortality. We studied temporal changes in hospital admission rates for atrial fibrillation using data from a prospective population-based cohort study spanning 2 decades (the Copenhagen City Heart Study). METHODS: The study included baseline data collected in 1981 through 1983 on 10,955 persons age 40 to 79 years and baseline data collected in 1991 through 1994 on 7212 persons age 40 to 79 years. We used hospital diagnosis data from the Danish National Hospital Discharge Register to determine the rate of first hospital admission for atrial fibrillation during 7 years following each of the 2 baseline data collecting periods. Changes in admission rates were analyzed using Cox proportional hazard models. RESULTS: During the 2 7-year periods, 379 subjects were admitted with a hospital diagnosis of atrial fibrillation. The rate of hospital admissions for atrial fibrillation increased among both men and women from the first to the second period (relative risk = 1.6; 95% confidence interval = 1.3-1.9 [adjusted for age, sex, prior myocardial infarction, arterial hypertension, diabetes mellitus, electrocardiographic left ventricular hypertrophy, decreased lung function, smoking, height, and weight]). CONCLUSION: During the latest 10 to 20 years, there has been a 60% increase in hospital admissions for atrial fibrillation independent of changes in known risk factors. This increase could result from changes in admission threshold or coding practices, or it could reflect a genuine increase in the population incidence of atrial fibrillation.

Intracardiac low-energy versus transthoracic high-energy direct-current cardioversion of atrial fibrillation: a randomised comparison.

Of 54 patients with long-standing atrial fibrillation (mean duration 8.3 months), 27 patients were randomised to transvenous low-energy intracardiac biphasic direct-current (DC) cardioversion (ICV) using a single-lead balloon-tipped catheter, and 27 patents were randomised to conventional high-energy transthoracic monophasic DC cardioversion (TCV). ICV was performed with increasing energy levels (7.5-10-12.5-15 J) during mild sedation. TCV was performed with 200-360-360 J during general anaesthesia. Cardioversion to sinus rhythm occurred in 93% (25/27) following ICV and in 67% (18/27) following TCV (p = 0.04). Due to the higher cardioversion rate following ICV, more patients were in sinus rhythm during 180 days of follow-up (log rank test, p = 0.04). Low-energy intracardiac cardioversion represents a highly efficacious alternative to high-energy transthoracic cardioversion.