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Lars Frost,1,2 Albert Marni Joensen,3 Ulla Dam-Schmidt,4 Ina Qvist,5 Margit Brinck,6 Axel Brandes,7,8 Ulla Davidsen,4 Ole Dyg Pedersen,9 Dorte Damgaard,10 Inge Mølgaard,11 Robert Bedsted,11 Anders Damgaard Møller Schlünsen,12 Miriam Grijota Chousa,12 Julie Andersen,12 Asger Roer Pedersen,1 Søren Paaske Johnsen,13 Nicklas Vinter1,13 1Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Cardiology, North Denmark Regional Hospital, Hjørring, Denmark; 4Department of Cardiology, Bispebjerg Hospital, Copenhagen University Hospitals, Copenhagen, Denmark; 5Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Cardiology, Odense University Hospital, Odense, Denmark; 7Department of Cardiology, Esbjerg Hospital – University Hospital of Southern Denmark, Esbjerg, Denmark; 8Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; 9Department of Cardiology, Zealand University Hospital, Roskilde, Denmark; 10Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 11Patient Representative, Aalborg and Roskilde, Denmark; 12The Danish Clinical Quality Program – National Clinical Registries (RKKP), Aarhus, Denmark; 13Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Lars Frost, Diagnostic Centre, University Clinic for Development of Innovative Patient Pathways, Silkeborg Regional Hospital; Department of Clinical Medicine, Aarhus University, Falkevej 3, Silkeborg, 8600, Denmark, Tel +45 23988590, Email larfrost@rm.dkAim: The Danish Atrial Fibrillation (AF) Registry monitors and supports improvement of quality of care for all AF patients in Denmark. This report describes the registry’s administrative and organizational structure, data sources, data flow, data analyses, annual reporting, and feedback between the registry, clinicians, and the administrative system. We also report the selection process of the quality indicators and the temporal trends in results from 2017– 2021.Methods and Results: The Danish AF Registry aims for complete registration and monitoring of care for all patients diagnosed with AF in Denmark. Administrative registries provide data on contacts to general practice, contacts to private cardiology practice, hospital contacts, medication prescriptions, updated vital status information, and biochemical test results. The Danish Stroke Registry provides information on stroke events. From 2017 to 2021, the proportion with a reported echocardiography among incident AF patients increased from 39.9% (95% CI: 39.3– 40.6) to 82.6% (95% CI: 82.1– 83.1). The initiation of oral anticoagulant therapy among patients with incident AF and a CHA2DS2-VASc score of ≥ 1 in men and ≥ 2 in women increased from 85.3% (95% CI: 84.6– 85.9) to 90.4% (95% CI: 89.9– 91.0). The 1-year and 2-year persistence increased from 85.2% (95% CI: 84.5– 85.9) to 88.7% (95% CI: 88.0– 89.3), and from 85.4% (95% CI: 84.7– 86.2) to 88.2% (95% CI: 87.5– 88.8), respectively. The 1-year risk of ischemic stroke among prevalent patients with AF decreased from 0.88% (95% CI: 0.83– 0.93) to 0.71% (95% CI: 0.66– 0.75). Variation in clinical performance between the five administrative Danish regions was reduced.Conclusion: Continuous nationwide monitoring of quality indicators for AF originating from administrative registries is feasible and supportive of improvements of quality of care.Keywords: atrial fibrillation, quality indicators, quality of care

Background and Aims: High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study is aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation., Methods: In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope., Results: The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P = .83). There were no between-group differences in atrial fibrillation exceeding 6 or 24 h, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71, 95% CI 1.13-2.59, P = .01)., Conclusions: Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis., Methods: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues., Discussion: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial., Trial Registration: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020., (© 2023. The Author(s).)

Introduction: Atrial fibrillation is the most common heart arrhythmia with a prevalence of approximately 2% in the western world. Atrial fibrillation is associated with an increased risk of death and morbidity. In many patients, a rate control strategy is recommended. The optimal heart rate target is disputed despite the results of the the RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient vs strict rate control II (RACE II) trial.Our primary objective will be to investigate the effect of lenient rate control strategy (<110 beats per minute (bpm) at rest) compared with strict rate control strategy (<80 bpm at rest) on quality of life in patients with persistent or permanent atrial fibrillation., Methods and Analysis: We plan a two-group, superiority randomised clinical trial. 350 outpatients with persistent or permanent atrial fibrillation will be recruited from four hospitals, across three regions in Denmark. Participants will be randomised 1:1 to a lenient medical rate control strategy (<110 bpm at rest) or a strict medical rate control strategy (<80 bpm at rest). The recruitment phase is planned to be 2 years with 3 years of follow-up. Recruitment is expected to start in January 2021. The primary outcome will be quality of life using the Short Form-36 (SF-36) questionnaire (physical component score). Secondary outcomes will be days alive outside hospital, symptom control using the Atrial Fibrillation Effect on Quality of Life, quality of life using the SF-36 questionnaire (mental component score) and serious adverse events. The primary assessment time point for all outcomes will be 1 year after randomisation., Ethics and Dissemination: Ethics approval was obtained through the ethics committee in Region Zealand. The design and findings will be published in peer-reviewed journals as well as be made available on ClinicalTrials.gov., Trial Registration Number: NCT04542785., Competing Interests: Competing interests: JBF (PI), IR, WB, EEN, FS-H, ODP, UG, CG and JCJ report no competing interests. MHO reports grants from Novo Nordic Foundation outside the submitted work. AB reports personal fees from Bayer, grants from Biotronik, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from MSD, grants from Theravance, outside the submitted work. UD reports a research grant from Bayer, personal fees from Pfizer, member of advisory board for Boehringer Ingelheim, member of advisory board for Merck, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICD) in Patients with Non-ischaemic Systolic Heart Failure (HF) on Mortality (DANISH) found no overall effect on all-cause mortality. The effect of ICD implantation on health-related quality of life (HRQoL) remains to be established as previous trials have demonstrated conflicting results. We investigated the impact of ICD implantation on HRQoL in patients with non-ischaemic systolic HF, a prespecified secondary endpoint in DANISH., Methods and Results: In DANISH, a total of 1116 patients with non-ischaemic systolic HF were randomly assigned (1:1) to ICD implantation or usual clinical care (control). Patients completed disease-specific HRQoL as assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ; 0-105, high indicating worse). Changes in HRQoL 8 months after randomization were assessed with a mixed-effects model. At randomization, MLHFQ was completed by 935 (84%) patients (n = 472 in the ICD group and n = 463 in the control group) and was reassessed in 274 (58%) and 292 (63%) patients, respectively after 8 months for the primary analysis. Patients in the ICD group vs. the control group had similar improvements in MLHFQ after 8 months [least square mean -7.0 vs. -4.2 (P = 0.13)]. A clinically relevant improvement (decrease ≥5) in the MLHFQ overall score at 8 months was observed in 151 patients in the ICD group and 148 patients in the control group [55% vs. 51%, respectively (P = 0.25)]., Conclusion: Implantable cardioverter-defibrillator implantation in patients with non-ischaemic systolic HF did not significantly alter HRQoL compared with patients randomized to usual clinical care., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography., Methods: 1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies., Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively., Conclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research., Competing Interests: The authors have declared that no competing interests exist.

Context: Thyroid dysfunction has been associated with both increased all-cause and cardiovascular mortality, but limited data are available on mild thyroid dysfunction and cause-specific mortality., Objective: The objective of the study was to examine the risk of all-cause mortality, major adverse cardiovascular events (MACEs), and cause-specific events in subjects with overt and subclinical thyroid dysfunction., Design: This was a retrospective cohort study., Setting and Participants: Participants in the study were subjects who underwent thyroid blood tests, without prior thyroid disease, consulting their general practitioner in 2000-2009 in Copenhagen, Denmark., Main Outcome Measure: All-cause mortality, MACEs, and cause-specific events identified in nationwide registries were measured., Results: A total of 47 327 (8.4%) deaths occurred among 563 700 included subjects [mean age 48.6 (SD ± 18.2) y; 39% males]. All-cause mortality was increased in overt and subclinical hyperthyroidism [age adjusted incidence rates of 16 and 15 per 1000 person-years, respectively; incidence rate ratios (IRRs) 1.25 [95% confidence interval (CI) 1.15-1.36] and 1.23 (95% CI 1.16-1.30)] compared with euthyroid (incidence rate of 12 per 1000 person-years). Risk of MACEs was elevated in overt and subclinical hyperthyroidism [IRRs 1.16 (95% CI 1.05-1.27) and 1.09 (95% CI 1.02-1.16)] driven by heart failure [IRRs 1.14 (95% CI 0.99-1.32) and 1.20 (95% CI 1.10-1.31)]. A reduction of all-cause mortality was observed in subclinical hypothyroidism with TSH of 5-10 mIU/L [IRR 0.92 (95% CI 0.86-0.98)]., Conclusions: Heart failure is the leading cause of an increased cardiovascular mortality in both overt and subclinical hyperthyroidism. Subclinical hypothyroidism with TSH 5-10 mIU/L might be associated with a lower risk of all-cause mortality.

Background and Purpose: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long-term cardiac monitoring., Methods: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis., Results: Eighty-five patients were monitored for a mean of 569 days (SD ±310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD ±48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC)., Conclusions: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Objective: We investigated the diagnostic value of exercise-induced increase in cardiac Troponin T (cTnT) in stable chest pain subjects., Methods: CTnT was measured before and 20 h after an exercise test in 157 subjects suspected of coronary artery disease (CAD)., Results: CAD subjects (n = 41) had higher baseline cTnT levels compared to non-CAD subjects (n = 116), 6.39 ng/l and 3.00 ng/l, respectively, p < 0.0001, and were more likely to increase in cTnT (70.7% versus 27.6%, p < 0.0001). Net Reclassification Index for the combined variable was 19%, p = 0.02., Conclusions: Exercise-induced increase in cTnT was found to be associated with CAD and cTnT measurements improved the diagnostic evaluation.

Aims: To examine the long-term risk of hyperthyroidism in patients admitted to hospital with new-onset AF. Hyperthyroidism is a well-known risk factor for atrial fibrillation (AF), but it is unknown whether new-onset AF predicts later-occurring hyperthyroidism., Methods and Results: All patients admitted with new-onset AF in Denmark from 1997-2009, and their present and subsequent use of anti-thyroid medication was identified by individual-level linkage of nationwide registries. Patients with previous thyroid diagnosis or thyroid medication use were excluded. Development of hyperthyroidism was assessed as initiation of methimazole or propylthiouracil up to a 13-year period. Risk of hyperthyroidism was analysed by Poisson regression models adjusted for important confounders such as amiodarone treatment. Non-AF individuals from the general population served as reference. A total of 145,623 patients with new-onset AF were included (mean age 66.4 years [SD ±13.2] and 55.3% males) of whom 3% (4,620 events; 62.2% women) developed hyperthyroidism in the post-hospitalization period compared to 1% (48,609 events; 82% women) in the general population (n = 3,866,889). In both women and men we found a significantly increased risk of hyperthyroidism associated with new-onset AF compared to individuals in the general population. The highest risk was found in middle-aged men and was consistently increased throughout the 13-year period of observation. The results were confirmed in a substudy analysis of 527,352 patients who had thyroid screening done., Conclusion: New-onset AF seems to be a predictor of hyperthyroidism. Increased focus on subsequent risk of hyperthyroidism in patients with new-onset AF is warranted.

Objectives: To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients., Design: Population based cohort study of general practice patients identified by linkage of nationwide registries at the individual level., Setting: Primary care patients in the city of Copenhagen., Subjects: Registry data for 586,460 adults who had their thyroid function evaluated for the first time by their general practitioner during 2000-10 and who were without previously recorded thyroid disease or atrial fibrillation., Main Outcome Measure: Poisson regression models used to estimate risk of atrial fibrillation by thyroid function., Results: Of the 586,460 individuals in the study population (mean (SD) age 50.2 (16.9) years, 39% men), 562,461 (96.0%) were euthyroid, 1670 (0.3%) had overt hypothyroidism, 12,087 (2.0%) had subclinical hypothyroidism, 3966 (0.7%) had overt hyperthyroidism, and 6276 (1.0%) had subclinical hyperthyroidism. Compared with the euthyroid individuals, the risk of atrial fibrillation increased with decreasing levels of thyroid stimulating hormone (TSH) from high normal euthyroidism (incidence rate ratio 1.12 (95% CI 1.03 to 1.21)) to subclinical hyperthyroidism with reduced TSH (1.16 (0.99 to 1.36)) and subclinical hyperthyroidism with supressed TSH (1.41 (1.25 to 1.59)). Both overt and subclinical hypothyroidism were associated with a lower risk of atrial fibrillation., Conclusion: The risk of atrial fibrillation was closely associated with thyroid activity, with a low risk in overt hypothyroidism, high risk in hyperthyroidism, and a TSH level dependent association with risk of atrial fibrillation across the spectrum of subclinical thyroid disease.

Background: Patients with heart failure (HF) and atrial fibrillation (AF) may differ from the larger HF population with respect to comorbidities, including renal impairment and overall prognosis. Associated cardiorenal interactions may mitigate the effects of pharmacological agents. Our primary objective was to assess the impact of mineralocorticoid receptor antagonists on cardiovascular mortality in patients with AF and HF enrolled in the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial., Methods and Results: All 1376 patients randomized in the AF-CHF trial were included. The median baseline creatinine was 105.2 (Q1 88.4, Q3 125.0) μmol/L, and the median estimated glomerular filtration rate was 62.3 (Q1 49.0, Q3 77.2) mL/min per 1.73 m(2). The renal function was moderately or severely impaired (ie, estimated glomerular filtration rate <60 mL/min per 1.73 m(2)) in 46.5% of patients. In multivariable analyses, increased creatinine was associated with worsening HF but not mortality. Mineralocorticoid receptor antagonists were prescribed in 44.8% and were independently associated with a 1.4-fold increase in total mortality (hazard ratio, 1.4; 95% CI [1.1-1.8]; P=0.005) and a 1.4-fold increase in cardiovascular mortality (hazard ratio, 1.4; 95% CI [1.1-1.9]; P=0.009). This was driven by an increased incidence of sudden cardiac death (hazard ratio, 2.0; 95% CI [1.3, 3.0]; P=0.001)., Conclusions: Renal dysfunction was highly prevalent in patients with AF and HF. Mineralocorticoid receptor antagonists were independently associated with an increased incidence of cardiovascular deaths, predominantly of presumed arrhythmic cause. Although these provocative findings merit prospective validation, they underscore the importance of careful monitoring of renal function and electrolytes in patients with AF and HF receiving mineralocorticoid receptor antagonists.

Background: We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months., Methods: The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo., Results: The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group. Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89). In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86). In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24)., Conclusion: In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).

Aims: The prognostic importance of atrial fibrillation (AF) in heart failure (HF) populations is controversial and may depend on patient selection. In the present study, we investigated the prognostic impact of AF in a large population with HF of various aetiologies., Methods and Results: We included 2881 patients admitted to hospital with symptoms of worsening HF over a 4-year period (2001-2004), all patients were participants in the Echocardiography and Heart Outcome Study (ECHOS). Patients were followed for up to 7 years for all-cause mortality stratified according to heart rhythm (sinus rhythm, paroxysmal, or chronic AF) and according to the presence of ischaemic heart disease (IHD). During follow-up, 1934 patients (67%) died. In HF patients with a history of IHD, chronic AF was associated with an increased risk of death [hazard ratio (HR) 1.44; 95% confidence interval (CI): 1.18-1.77; P < 0.001). In contrast, in patients without IHD, chronic AF was not associated with an increased mortality risk (HR 0.88; 95% CI: 0.71-1.09; P = 0.25). There was significant interaction between the aetiology of HF and the prognostic importance of chronic AF (P(interaction) = 0.003)., Conclusion: In patients with HF, AF is associated with an increased risk of death only in patients with underlying IHD.

Objectives: The goal of this study was to evaluate the relationship between the presence of sinus rhythm and outcomes in patients with a history of congestive heart failure (CHF) and atrial fibrillation (AF)., Background: The value of sinus rhythm maintenance in patients with AF and heart failure (HF) is uncertain., Methods: A total of 1,376 patients with AF, ejection fraction < or =35%, and heart failure symptoms were randomized to a rhythm- or rate-control strategy. Detailed efficacy analyses were used to evaluate the independent effects of treatment strategy and the presence of sinus rhythm on cardiovascular outcomes., Results: Overall, 445 (32%) patients died and 402 (29%) experienced worsening HF. The rhythm-control strategy was not predictive of cardiovascular mortality (hazard ratio [HR]: 0.90, 95% confidence interval [CI]: 0.70 to 1.16; p = 0.41), all-cause death (HR: 0.86, 95% CI: 0.69 to 1.08; p = 0.19), or worsening HF (HR: 0.86, 95% CI: 0.68 to 1.10; p = 0.23). In analyses devised to isolate the effect of underlying rhythm, sinus rhythm was not associated with cardiovascular mortality [HR: 1.22, 95% CI: 0.80 to 1.87; p = 0.35), total mortality [HR: 1.11, 95% CI: 0.78 to 1.58; p = 0.57), or worsening HF [HR: 0.62, 95% CI: 0.37 to 1.02; p = 0.059)., Conclusions: A rhythm-control strategy or the presence of sinus rhythm are not associated with better outcomes in patients with AF and CHF., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied., Methods: We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes., Results: A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup., Conclusions: In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.), (2008 Massachusetts Medical Society)

Aims: Atrial fibrillation (AF) is a risk factor for death in patients with a myocardial infarction, but highly variable results are reported in patients with heart failure. We studied the prognostic impact of AF in heart failure patients with and without ischaemic heart disease., Methods and Results: During a period of 2 years, 3587 patients admitted to hospital because of heart failure were included in this study. All patients were examined by echocardiography and the presence of AF was recorded. Follow-up was available for 8 years. Twenty four percent of those discharged alive from hospital had AF. After 4 and 8 years of follow-up, mortality was higher in patients with AF than in patients without, 56 vs. 52% and 77 vs. 73%, respectively. Cox multivariable regression analysis showed a small but significant importance of AF for long-term mortality [hazard ratio (HR) 1.12, 95% confidence limits (CI), 1.02-1.23, P=0.018]. There was a significant interaction between the importance of AF and the presence of ischaemic heart disease (P=0.034). In patients with AF at the time of discharge and ischaemic heart disease, HR was 1.25 (95% CI: 1.09-1.42) and P<0.001; in patients with AF at discharge and without ischaemic heart disease, HR was 1.01 (95% CI: 0.88-1.16) and P=0.88., Conclusion: AF is associated with increased risk of death only in patients with ischaemic heart disease. This finding may explain the variable results of studies of the prognosis associated with AF in heart failure.

Aims: Atrial fibrillation (AF) is a common complication in patients with acute myocardial infarction and is associated with an increase in the risk of death. The excess mortality associated with AF complicating acute myocardial infarction has not been studied in detail. Observations indicate that AF facilitates induction of ventricular arrhythmias, which may increase the risk of sudden cardiovascular death (SCD). A close examination of the mode of death could potentially provide useful knowledge to guide further investigations and treatments., Methods and Results: We analysed the relation between AF/atrial flutter (AFL) and modes of death in 5983 consecutive patients discharged alive after an acute myocardial infarction screened in the TRAndolapril Cardiac Evaluation registry. This cohort of patients with an enzyme-verified acute myocardial infarction was admitted to 27 centres in 1990-92. Survival status was obtained 2 years after screening of the last patient. An independent endpoint committee assessed the modes of death. Left ventricular ejection fraction was determined in all the screened patients and information about presence or absence of AF/AFL was prospectively collected. Sustained or paroxysmal AF/AFL was observed in 1149 patients (19%) during hospitalization. During follow-up, 1659 patients (34%) died: 482 (50%) patients with AF/AFL and 1177 (30%) patients without AF/AFL, P<0.001. SCD occurred in 536, non-SCD occurred in 725, and 398 died of non-cardiovascular causes (includes 142 unclassifiable cases). The adjusted risk ratio of AF/AFL for total mortality was 1.33 (95% CI: 1.19-1.49; P<0.0001) and the risk ratio for SCD was 1.31 (95% CI: 1.07-1.60; P<0.009). The adjusted risk ratio of AF/AFL for non-SCD was 1.43 (95% CI: 1.21-1.70; P<0.0001)., Conclusion: The excess mortality observed in patients with AF/AFL following acute myocardial infarction is due to a significant increase in both SCD and non-SCD.

Atrial fibrillation is the most common sustained cardiac arrhythmia and is a frequent reason for antiarrhythmic therapy. Existing antiarrhythmic drugs have important side effects and presently the therapy to maintain sinus rhythm is not superior to a strategy of controlling excessive heart rate. This review summarises current strategies to improve antiarrhythmic therapy for atrial fibrillation. The most important strategies are: i) to develop drugs without proarrhythmic effects--development of drugs devoid of QT prolonging potential is the main strategy; ii) multiple channel-blocking drugs--inspired by the efficacy of amiodarone, several drugs are being developed that have similar electrophysiological properties as amiodarone, but without the extracardiac side effects; iii) drugs that act exclusively in the atria--the atria contain specific potassium channels, and several drugs that act only on these channels are in development; and iv) antiarrhythmic therapy without effects on ion channels--inhibition of the renin-angiotensin system and steroid therapy has been shown to have some effect in the treatment of atrial fibrillation. Many drugs are in development and the therapeutic scenario for treatment of atrial fibrillation may change quickly.

Background: Reports on the prognostic importance of atrial fibrillation following myocardial infarction have provided considerable variation in results. Thus, this study examined the impact of left ventricular systolic function and congestive heart failure on the prognostic importance of atrial fibrillation in acute myocardial infarction patients that might explain previous discrepancies., Methods: The study population was 6676 patients consecutively admitted to hospital with acute myocardial infarction. Information on the presence of atrial fibrillation/flutter, left ventricular systolic function and congestive heart failure were prospectively collected. Mortality was followed for 5 years., Results: In patients with left ventricular ejection fraction<0.25, atrial fibrillation/atrial flutter was associated with an increased in-hospital mortality (OR=1.8 (1.1-3.2); p<0.05) but not an increased 30-day mortality. In patients with 0.250.35. In patients with congestive heart failure, atrial fibrillation/atrial flutter was associated with an increased in-hospital mortality (OR=1.5 (1.2-1.9); p<0.001) and increased 30-day mortality (OR=1.4 (1.1-1.7); p<0.001) but not in patients without congestive heart failure. In hospital survivors, atrial fibrillation/atrial flutter was associated with an increased long-term mortality in all subgroups except those with left ventricular ejection fraction<0.25., Conclusions: Atrial fibrillation/atrial flutter is primarily associated with increased in-hospital mortality in heart failure patients. Long-term mortality is increased in all subgroups except those with left ventricular ejection fraction<25%.

The prevalence of arrhythmia in the population is increasing as more people survive for longer with cardiovascular disease. It was once thought that antiarrhythmic therapy could save life, however, it is now evident that antiarrhythmic therapy should be administrated with the purpose of symptomatic relief. Since many patients experience a decrease in physical performance as well as a diminished quality of life during arrhythmia there is still a need for antiarrhythmic drug therapy. The development of new antiarrhythmic agents has changed the focus from class I to class III agents since it became evident that with class I drug therapy the prevalence of mortality is considerably higher. This review focuses on the benefits and risks of known and newer class III antiarrhythmic agents. The benefits discussed include the ability to maintain sinus rhythm in persistent atrial fibrillation patients, and reducing the need for implantable cardioverter defibrillator shock/antitachycardia therapy, since no class III antiarrhythmic agents have proven survival benefit. The risks discussed mainly focus on pro-arrhythmia as torsade de pointes ventricular tachycardia.

Atrial fibrillation is a growing health problem and the most common cardiac arrhythmia, affecting 5% of persons above the age of 65 years. The number of hospital discharges for atrial fibrillation has more than doubled in the past decade. It occurs very often in patients with congestive heart failure and the prevalence increases with the severity of the disease. These two conditions seem to be linked together, and congestive heart failure may either be the cause or the consequence of atrial fibrillation. The prognosis of atrial fibrillation is controversial, but studies indicate that atrial fibrillation is a risk factor in congestive heart failure patients. In the last 10-15 years, significant advances in the treatment of heart failure have improved survival, whereas effective management of atrial fibrillation in heart failure patients still awaits similar progress. Empirically, two strategies have evolved for treatment of atrial fibrillation: 1) rhythm control, which means conversion to sinus rhythm and maintenance of sinus rhythm; and 2) rate control, which means reduction of heart rate to an acceptable frequency. It is unknown whether one of these strategies is better than the other. In this review the authors discuss the prevalence, impact, and treatment of atrial fibrillation in heart failure patients.

Background: Atrial fibrillation is a common arrhythmia in patients with left ventricular dysfunction associated with increased morbidity and mortality. The present study investigated the potential of dofetilide to restore and maintain sinus rhythm in patients with left ventricular dysfunction, which might reduce mortality and hospitalizations., Methods and Results: In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in atrial fibrillation (AF) or atrial flutter (AFl) at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo ( P < 0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinusrhythm (independent of study treatment) was associated with a significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P < 0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P < or = 0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P < or = 0.02) rehospitalization., Conclusions: Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm--on placebo or dofetilide--is associated with improved survival.

Although arrhythmic death is a common cause of death in patients with congestive heart failure (CHF), numerous trials involving prophylactic antiarrhythmic drug treatment have yielded few gains. To date, only beta-blockers have shown a distinct mortality-reducing effect and despite the antiarrythmic effect of gamma-blockers, results point towards causes other than the antiarrhythmic effect in obtaining this beneficial effect. Atrial fibrillation is an often-encountered arrhythmia in patients with CHF and recent trials have cast doubt on the present treatment strategy of persistently striving to obtain sinus rhythm. This paper outlines the results of the large clinical trials dealing with antiarrhythmic drug treatment in CHF patients with or without atrial fibrillation and certain subgroup analysis and future treatment possibilities are discussed.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Mortality, and especially morbidity caused by AF, are major and growing health problems in the western world. AF is strongly associated with arterial hypertension, congestive heart failure, valvular heart disease, ischaemic heart disease, and with prevalence increasing with age. A variety of drugs have been used to terminate or prevent AF but, as many antiarrhythmic agents have the potential life-threatening pro-arrhythmia, safety problems remain. Dofetilide (Tikosyn, Pfizer), a new Vaughan Williams class III antiarrhythmic agent, has been developed and approved for the treatment of AF. In contrast to most antiarrhythmic agents, the development programme included two safety studies in high-risk patients. Dofetilide is effective and safe when an elaborate procedure for dosing is implemented. Along with amiodarone and betablockers, dofetilide is the only antiarrhythmic drug, which is recommended by guidelines for the treatment of AF in a wide range of patients.

Atrial fibrillation is the most commonly sustained cardiac arrhythmia and a common reason for mortality and morbidity. Atrial fibrillation causes disease for three reasons: i) the ventricular rate is often high, which leads to symptoms ranging from discomfort to life threatening heart failure; ii) the rhythm causes loss of atrioventricular synchrony, which reduces diastolic filling and may lead to heart failure; and iii) atrial contraction is lost leading to stagnant blood that again may lead to atrial thrombi and peripheral embolism. Thus, the treatment of atrial fibrillation is focused on the maintenance of sinus rhythm, rate control and prevention of embolism. For the maintenance of sinus rhythm, all drugs under current development are potassium channel blockers; the so-called class III anti-arrhythmic drugs. Those which have been further investigated appear to be valuable for maintenance of sinus rhythm but all carry a significant risk of pro-arrhythmia, in particular Torsade de Pointe ventricular tachycardia. Rate control has been a focus of treatment for many years and several very old drugs, including digoxin, are used for this. There is, to the author's knowledge, no current effort for evaluating new drugs for this indication. Prevention of embolism has for many years been obtained with vitamin K antagonists for which the clinical evidence is overwhelming. Previous attempts to replace vitamin K antagonists with aspirin have not been fruitful. A large number of newer anticoagulation regimes are in development, but to the author's knowledge only a single thrombin inhibitor is actively being developed for atrial fibrillation.

Background: In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations., Methods and Results: In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (P<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P

To obtain a further understanding of the nature of the multiexponential T(2) relaxation seen in muscle tissue water (myowater), relaxation measurements were carried out on whole, minced, and homogenized pork of three different qualities with regard to water-holding capacity (normal, red soft exudative, and dark firm dry). Whole, minced, and homogenized pork all resulted in multiexponential T(2) relaxation (three components) independently of the quality, even though microscopic studies on homogenized meat revealed considerable disruption of the macroscopic structure. This states that the relaxation behavior in meat cannot be explained by intra-/extracellular compartmentalization of the water as suggested in earlier studies. Subsequent studies of T(2) relaxation in either whole meat, where the structure integrity was changed by the introduction of dimethyl sulfoxide (membrane disruption) or urea (protein denaturation), or minced meat with added NaCl (inter-/intraprotein interactions) lead to the suggestion that in whole meat (i) the fastest relaxation component reflects water tightly associated with macromolecules, (ii) the intermediate relaxation component reflects water located within highly organized protein structures, for example, water in tertiary and/or quaternary protein structures and spatials with high myofibrillar protein densities including actin and myosin filament structures, and (iii) the slowest relaxation component reflects the extra-myofibrillar water containing the sarcoplasmatic protein fraction. Finally, relaxation patterns in heat-set gels of superprecipitated actomyosin and bovine serum albumin similar to that identified in whole meat support the proposed nature of T(2) relaxation in muscle myowater.

Background: Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown., Methods and Results: We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively, P<0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P<0.01)., Conclusions: The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.

Aims: To investigate the occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction., Methods and Results: The occurrence and prognostic significance of atrial fibrillation/-flutter were studied in 6676 consecutive patients with acute myocardial infarction screened in 27 centres in Denmark for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study. Information about occurrence of atrial fibrillation/-flutter during hospitalization was prospectively collected for the following three periods: day 1-2, day 3-4 and from day 5 until discharge. A total of 1395 patients (21%) suffered from atrial fibrillation/-flutter in one or more of the specified periods during hospitalization. Patients with atrial fibrillation/-flutter were significantly older, a significantly greater proportion were women, left ventricular systolic dysfunction was more extensive, thrombolytic therapy was received less frequently, and anterior Q wave myocardial infarction was experienced more frequently than patients without atrial fibrillation/-flutter. History of acute myocardial infarction and/or angina pectoris was similar in patients with and without atrial fibrillation/-flutter, whereas significantly more patients with atrial fibrillation/-flutter had a history of hypertension, congestive heart failure, diabetes mellitus, pulmonary disease and stroke. The unadjusted in-hospital mortality rate was significantly higher in patients with atrial fibrillation/-flutter in one or more of the specified periods during hospitalization (18%) than in patients without atrial fibrillation/-flutter (9%), P<0.001. After adjustment for baseline characteristics, the presence of atrial fibrillation/-flutter was still associated with increased in-hospital mortality; odds ratio=1.5 (95% Cl: 1.2-1.8), P<0.001. In patients surviving hospitalization, the unadjusted 5-year mortality rate was also significantly higher in patients suffering from atrial fibrillation/-flutter (56%) than in patients without atrial fibrillation/-flutter (34%), P<0.001. After adjustment for important prognostic baseline characteristics, the presence of atrial fibrillation/-flutter was still associated with an increased mortality, relative risk=1.3 (95% Cl: 1.2-1.4). Subgroup analysis revealed that sustained atrial fibrillation/-flutter during hospitalization was associated with the highest risk of dying, relative risk=1.4 (95% Cl: 1.2-1.7)., Conclusion: Atrial fibrillation/-flutter often occurs after acute myocardial infarction and our analysis demonstrated that it was an independent predictor of an increased short and long-term mortality., (Copyright 1999 The European Society of Cardiology.)

Background: Large-scale studies have indicated that treatment with angiotensin converting enzyme (ACE) inhibitors reduces the incidence of myocardial infarction and unstable angina pectoris among patients with recent myocardial infarction and moderate left ventricular dysfunction. An improved endogenous fibrinolysis might be responsible for this effect., Objectives: To investigate the effect of trandolapril on the endogenous tissue-type plasminogen activator (t-PA) in patients with a recent myocardial infarction and moderate left ventricular dysfunction., Methods: Fifty-six patients with acute myocardial infarction and a wall motion index < or = 1.2 were allocated randomly either to administration of trandolapril or to placebo. When possible, the study drug dose was increased gradually to 4 mg trandolapril or a corresponding amount of placebo during the first month after randomization. Blood samples for determination of the variables of the fibrinolytic system, ACE activity and ACE genotype were collected prior to randomization and during out-patient visits in months 1, 3, 6, 9 and 12. After the subject had fasted overnight, blood samples were collected in the morning (0800-1000 h) after the subject had rested supine for at least 15 min, from a venous cannula inserted into the forearm. The effect of trandolapril on the fibrinolytic variables was evaluated by calculating the area under the curve (AUC1-12) from month 1 to month 12., Results: The trandolapril group and the placebo group were similar with respect to baseline clinical characteristics, baseline fibrinolytic variables and baseline plasma ACE activity. The trandolapril group did not differ significantly from the placebo group with respect to AUC1-12 t-PA antigen [11.67 (3.95-26.45) versus 10.34 ng/ml (3.71-19.62), P = 0.19] and AUC1-12 plasminogen activator inhibitor type-1 (PAI-1) antigen [27.57 (8.38-89.49) versus 24.40 ng/ml (7.94-90.62), P = 0.92]. A significant and clear trend in variation with time of t-PA antigen was observed for the trandolapril group, but not for the placebo group. The fibrinolytic variables were similar at baseline for the different ACE genotype insertion (I) and deletion (D) groups (II, ID and DD). Trandolapril treatment was associated with a significant (P < 0.04) increase in the AUC1-12 of t-PA antigen in the ID group compared with that of the placebo-treated ID group, whereas PAI-1 antigen concentration did not differ between the groups. Trandolapril treatment was not associated with any significant change in the fibrinolytic variables for the other genotype groups., Conclusions: Chronic ACE-inhibitor treatment with trandolapril was not associated with any significant difference in the blood concentrations of t-PA and PAI-1 compared with placebo. The suggested specific interaction between ACE inhibition and the increase in t-PA in patients with ACE genotype ID will require further confirmation.

A case of a twenty-nine year old woman with ischaemic stroke documented by Magnetic Resonance Imaging scanning is reported. As no embolic source was identified, it was most likely that the ischaemic stroke was caused by in situ arterial thrombosis. Except for a history of cardiovascular disease among her grandparents, she did not exhibit any of the classical risk factors for ischaemic stroke. Therefore, it is of interest that she had high serum concentrations of anticardiolipin antibodies and was a heterozygous carrier of the factor V Leiden mutation. It is possible that the combination of anticardiolipin antibodies and factor V Leiden mutation results in a procoagulant condition of the circulating blood, which in case of minor triggers may cause arterial occlusion. This mechanism may be responsible for the development of ischaemic stroke in the described case.

Objective: To determine whether there was a relation between plasma resistance to activated protein C and the coagulation activation induced during thrombolysis with 100 mg alteplase in 25 patients with acute ischaemic heart disease., Methods: Blood samples were collected before (t = 0 h), during (t = 2.25 h), and after (t = 4 h, t = 12 h, and t = 24 h) thrombolysis to examine the relation between baseline activated protein C resistance ratio and markers of coagulation activation-that is, thrombinantithrombin III-complexes and prothrombin fragment 1 + 2 generated during thrombolysis., Results: There was a negative correlation between activated protein C resistance ratio and area under the curve of thrombin-antithrombin III-complexes (rs = - 0.60; P < 0.003) and there was a trend to a negative correlation between activated protein C resistance ratio and area under the curve of prothrombin fragment 1 + 2 (rs = - 0.37; P = 0.07). This accorded with the negative correlation between activated protein C resistance ratio and the peak value of thrombin-antithrombin III-complexes (rs = - 0.55; P < 0.005) and between activated protein C resistance ratio and the peak value of prothrombin fragment 1 + 2 (rs = - 0.42; P < 0.04). Components of the protein C/S system or known inhibitors of activated protein C may influence the activated protein C resistance ratio. There were no associations between the activated protein C resistance ratio and protein C, protein C inhibitor, or plasminogen activator inhibitor type-1, whereas there was a trend to a negative correlation between activated protein C resistance ratio and protein S., Conclusions: The results indicate that plasma resistance to activated protein C may be one of the main mechanisms regulating the activation of coagulation induced by thrombolysis. This study suggests that it may be possible to single out individuals with a high risk of reocclusion before the start of thrombolytic therapy.

Left ventricular (LV) systolic function and congestive heart failure (CHF) are important predictors of long-term mortality after acute myocardial infarction. The importance of transient CHF and the interaction of CHF and LV function on prognosis has not been studied in detail previously. In the TRAndolapril Cardiac Evaluation Study, 6,676 consecutive patients with acute myocardial infarction 1 to 6 days earlier had LV systolic function quantified as wall motion index (echocardiography), which is closely correlated to LV ejection fraction. To study the interaction of CHF and wall motion index on long-term mortality, separate analyses were performed in patients with different levels of LV function. Risk ratio (95% confidence intervals [CI]) were determined from proportional hazard models subgrouped by wall motion index or CHF adjusted for age and gender. Heart failure was separated into transient or persistent. Wall motion index and CHF are correlated. Furthermore, there is an interaction between wall motion index and CHF. The prognostic importance of wall motion index depends on whether patients have CHF or not: the risk ratio associated with decreasing 1 wall motion index unit is 3.0 (2.6 to 3.4) in patients with CHF, and 2.2 (1.7 to 2.9) in patients without CHF when adjusted for age and gender. Similarly, the prognostic importance of CHF depends on the level of wall motion index: the risk ratio associated with CHF is 3.9 (1.8 to 8.3) when the wall motion index is <0.8 and 1.9 (1.5 to 2.3) when the wall motion index is >1.6. Transient CHF is an independent risk factor (risk ratio 1.5, confidence interval [CI] 1.3 to 1.8) although milder than persistent CHF (risk ratio 2.8, CI 2.5 to 3.2).

The aim of the present study was to find out whether plasminogen activator inhibitor type-1 (PAI-1) controls the formation of plasmin in patients with ischaemic heart disease. We examined PAI activity, PAI-1 antigen, tissue type plasminogen activator (t-PA) activity, t-PA antigen, plasmin-alpha2-antiplasmin complex (PAP-complex) and fibrin degradation products D-dimer in 62 patients before (unstimulated) and after infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; stimulated). DDAVP was used in a standardized dose to trigger the release of t-PA from the vascular endothelium. We observed that under basal conditions (unstimulated) median plasma t-PA activity for the whole group of patients was 86.5 mIU/ml (0-900), and after stimulation 2550 mIU/ml (0-6800), P < 0.0001; median plasma concentration of t-PA antigen was 14.7 ng/ml (7.0-115.5) under basal conditions, and after stimulation 34.1 ng/ml (15.8-58.6), P < 0.0001; median plasma PAI activity was 16.9 IU/ml (1.5-144.8) under basal conditions, and after stimulation 3.1 IU/ml (0-118.5), P < 0.0001; median plasma concentration of PAI-1 antigen was 21.5 ng/ml (8.1-132.2) under basal conditions, and after stimulation 14.9 ng/ml (4.8-149.0), P < 0.0001; the median plasma concentration of PAP-complex was 469.5 ng/ml (185.0-1802.0) under basal conditions, and after stimulation 695.5 (243.0-2292.0), P < 0.0001; median plasma concentration of D-dimer was 298.0 ng/ml (103.0-948.0) under basal conditions, and after stimulation 296.5 ng/ml (97.0-917.0), P < 0.0008.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Impaired endogenous tissue-type plasminogen activator (t-PA)-mediated fibrinolysis may be involved in the evolution of myocardial infarction. t-PA-mediated fibrinolysis is believed to depend on the amount of active t-PA present in the circulation. Accordingly, we investigated the possible mechanisms responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease., Methods: Forty-five survivors of acute myocardial infarction were examined 8 weeks after discharge from hospital. Intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; 0.4 micrograms/kg bodyweight) was used to stimulate the endogenous fibrinolytic system, and blood samples were collected before and after infusion. We compared the response of the t-PA-plasminogen activator inhibitor type-1 (PAI-1) fibrinolytic system in patients with preinfusion levels of active t-PA below or at the detection limit of the assay with that in patients with higher preinfusion levels of active t-PA., Results: All patients responded to DDAVP infusion with an increase in plasma concentration of t-PA antigen. This response did not differ between the two groups. In contrast, the preinfusion levels of PAI activity were significantly higher in patients with undetectable plasma levels of active t-PA compared with patients with higher levels of active t-PA (22.3 versus 12.8 IU/ml; P < 0.01). Subgroup analyses demonstrated that patients treated with diuretics had significantly higher plasma concentrations of PAI-1 antigen (28.5 versus 17.9 ng/ml; P < 0.03) and a trend towards higher PAI activity (24.0 versus 14.6 IU/ml; P = 0.07) compared with patients not receiving diuretics., Conclusion: Our study strongly suggests that a high plasma level of PAI-1, the main inhibitor of t-PA, is responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease, and that treatment with diuretics may be associated with an unfavourable effect on the fibrinolytic system.

Defective fibrinolysis may constitute a risk for the development of myocardial infarction in patients with ischaemic heart disease. We studied prospectively the factor XII-dependent plasminogen proactivator system in 49 survivors of an acute myocardial infarction. Blood samples were collected 8 weeks after hospital discharge. The factor XII-dependent fibrinolytic activity in the specimens was determined on fibrin plates after complete immuno-inhibition of the urokinase-like and the t-PA related fibrinolytic systems. During the subsequent follow-up period of 2.4 years, 10 patients developed recurrent myocardial infarction, whereas the remaining 39 patients did not. The reinfarction group of patients had a significantly lower median factor XII-dependent fibrinolytic activity (24.9 blood activating units (BAU).ml-1) than the patients without a relapse (41.9 BAU.ml-1, P < 0.02). Plasma concentrations of factor XII did not deviate significantly between the groups (P > 0.05), whereas the median plasma concentrations of prekallikrein was slightly lower in the reinfarction group (90%) than in the non-reinfarction group of patients (105%, P < 0.02). These observations point to an association between a depressed factor XII-dependent fibrinolytic activity and an enhanced risk of reinfarction in patients with a previous episode of acute myocardial infarction.

In an open prospective study with therapeutic monitoring, 34 women with climacteric symptoms, FSH > 40 IU/L and LH > 25 IU/L were treated for 12 months with an estradiol-depot-patch (Estraderm TTS) 50 micrograms twice a week and medroxyprogesterone acetate 10 mg tablets from 12th to 25th day of cycle. During the first months a significant improvement was seen in hot flushes and other climacteric inconveniences in terms of Kupperman's menopause index. During the study period FSH and LH were suppressed and the estrogen values were normalized. The fraction of free estradiol compared to protein bound estradiol remained unchanged during the whole treatment. The serum-lipids and serum-SHBG at inclusion were within normal limits and did not change during 12 months of treatment. Thus from these parameters no sign of any liver induction was seen. Ten patients had short term skin symptoms while four withdrew from the study because of persistent skin symptoms. Nine patients withdrew from the study, in five cases this was related to the therapy while in the other four it was due to other causes. Twenty-five (74%) women wished to continue the treatment after 12 months.

Two brothers both with hypertrophic obstructive cardiomyopathy, one of them also with neurofibromatosis are described. Only a few cases with this combination of diseases have been reported. The possibility of a coincidence or a causal relationship is mentioned. The importance of echocardiography in persons with cardiac murmurs is emphasized even in cases where the electrocardiogram and thoracic x-ray are normal.

As it has been shown that re-epithelialization of partial skin thickness wounds can be accelerated if the wound is kept moist, a prospective, randomized clinical study compared the water vapour-semipermeable polyurethane film, Opsite, with the conventional impregnated gauze dressing, Jelonet, in the treatment of outpatient partial skin thickness burns. Fifty-five patients were included: 30 were treated with the polyurethane film and 25 with the conventional dressing. The patients were followed at regular intervals until healing had occurred and were seen 3 months later for evaluation of residual scars and pigmentation. The burns treated with polyurethane films healed with a median of 10 days, while the conventionally treated burns healed with a median of 7 days (P greater than 0.05). Residual scars were noted in 21 per cent of the patients treated with polyurethane films and in 8 per cent treated conventionally (P greater than 0.05). Prophylactic methods should be publicly stressed since one-quarter of the patients were children of 3 years or less who were scalded by split hot liquids. Furthermore the patients' wounds were only briefly cooled before attending medical care. With small burns we advise that cooling should be prolonged until the pain fades then professional assistance should be sought.

The courses of 945 deliveries in which the infant weighed greater than or equal to 3,800 g are reviewed retrospectively with comparison between the deliveries which began spontaneously and the induced deliveries. In the deliveries which were induced on account of a suspected large foetus, the frequency of emergency Cesarean section was tripled and the frequency of vacuum extraction was doubled. Significantly more infants had Apgar scores of less than 7 after one minute than in the deliveries which began spontaneously. It is concluded that induction of labour is not indicated in cases where a large foetus is suspected.

The effect transcutaneous oestradiol for four months supplemented by medroxyprogesterone (Perlutex) from the 12th to 26th day of every month was assessed in an open uncontrolled prospective investigation in 34 women with menopausal symptoms and follicle stimulating hormone greater than 40 international units and luteinizing hormone greater than 25 international units. A marked effect was found on sweating and hot flushes and other menopausal complaints as expressed by Kupperman's menopausal index. Serum oestradiol increased during the first two months to follicular phase values and this was followed by an unexplained decrease after the fourth month which did not, however, result in aggravation of the symptoms. No alterations were found in steroid-hormone-binding globulin, lipids and body weight. Whether the patients placed the plasters in the hip or abdominal regions was found to be of no significance. Seventeen patients had no side effects of the treatment. Nine patients had transient skin symptoms which disappeared spontaneously. Five patients had mastalgia which disappeared after reduction of the Perlutex dose. One patient developed metrorrhagia. A total of three patients abandoned the treatment: one on account of skin symptoms, one on account of high blood pressure and a third on account of psychiatric symptoms which were unrelated to the treatment. A total of 28 patients wanted to continue treatment after the fourth month.

The increasing popularity of skateboards and rollerskates has resulted in an increased number of contacts with the casualty department in Denmark after accidents. As part of the Danish share in the EHLASS project (European Home and Leisure Surveillance System), 120,000 consecutive contacts with the casualty departments were reviewed. Out of these 516 were due to accidents with skateboards and rollerskates (181/335). A total of 194 of these injuries (38%) were fractures and 80% of these were in the upper limbs. Twenty fractures required reposition under general anaesthesia and two required osteosynthesis. Nine patients were admitted for observation for concussion. One patient had sustained rupture of the spleen and splenectomy was necessary. A total of 44 patients were admitted. None of the 516 patients had employed protective equipment on the injured region. Considerable reduction in the number of injuries could probably be produced by employment of suitable protective equipment.

Absorption of solutions containing 17-beta-oestradiol (E2) in absolute alcohol and progesterone (P) in absolute alcohol was investigated in six postmenopausal women. These preparations were applied to the skin of the forearm and the abdomen. 1 mg E2 was applied twice daily to the left forearm (RAS) for 28 days. After an interval of one week, the treatment was continued with 1 mg E2 twice daily for 28 days in the epigastric region (RE). From the 14th to the 28th day, this treatment was supplemented by 10 mg P twice daily partly on the right forearm and partly on the epigastrium. The 24-hour absorptions of E2 and P were investigated: E2 on the first and fourteenth days and P on the fourteenth day in both periods. On days 1, 7, 14, 21 and 28, plasma E2, oestrone (E1) and oestrone sulphate (E1SO4) were investigated for hormone application. Statistically significant absorption of E2 was found after 24 hours (p less than 0.05) and significantly greater absorption from RAS than RE (p less than 0.005). No systematic variation in plasma E2 was found during the period of investigation on RAS or RE. P was not absorbed. No local side effects were registered. It is concluded that E2 dissolved in absolute alcohol is clinically employable for treatment of postmenopausal women but that P is of no value in the dosage employed here. Further investigations of transcutaneous absorption of P are desirable.