Reference ranges for ambulatory heart rate measurements in a middle-aged population.

BACKGROUND: Elevated heart rate (HR) predicts cardiovascular disease and mortality, but there are no established normal limits for ambulatory HR. We used data from the Swedish CArdioPulmonary Imaging Study to determine reference ranges for ambulatory HR in a middle-aged population. We also studied clinical correlates of ambulatory HR. METHODS: A 24-hour ECG was registered in 5809 atrial fibrillation-free individuals, aged 50-65 years. A healthy subset (n=3942) was used to establish reference values (excluding persons with beta-blockers, cardiovascular disease, hypertension, heart failure, anaemia, diabetes, sleep apnoea or chronic obstructive pulmonary disease).Minimum HR was defined as the lowest 1-minute HR. Reference ranges are reported as means±SDs and 2.5th-97.5th percentiles. Clinical correlates of ambulatory HR were analysed with multivariable linear regression. RESULTS: The average mean and minimum HRs were 73±9 and 48±7 beats per minute (bpm) in men and 76±8 and 51±7 bpm in women; the reference range for mean ambulatory HR was 57-90 bpm in men and 61-92 bpm in women. Average daytime and night-time HRs are also reported. Clinical correlates, including age, sex, height, body mass index, physical activity, smoking, alcohol intake, diabetes, hypertension, haemoglobin level, use of beta-blockers, estimated glomerular filtration rate, per cent of predicted forced expiratory volume in 1 s and coronary artery calcium score, explained <15% of the interindividual differences in HR. CONCLUSION: Ambulatory HR varies widely in healthy middle-aged individuals, a finding with relevance for the management of patients with a perception of tachycardia. Differences in ambulatory HR between individuals are largely independent of common clinical correlates.

P-wave characteristics as electrocardiographic markers of atrial abnormality in prediction of incident atrial fibrillation - The Malmö Preventive Project.

BACKGROUND: P-wave indices reflect atrial abnormalities contributing to atrial fibrillation (AF). We aimed to assess a comprehensive set of P-wave characteristics for prediction of incident AF in a population-based setting. METHODS: Malmö Preventative Project (MPP) participants were reexamined in 2002-2006 with electrocardiographic (ECG) and echocardiographic examinations and followed for 5 years. AF-free subjects (n = 983, age 70 ± 5 years, 38% females) with sinus rhythm ECGs were included in the study. ECGs were digitally processed using the Glasgow algorithm. P-wave duration, axis, dispersion, P-terminal force in lead V1 and interatrial block (IAB) were evaluated. ECG risk score combining the morphology, voltage and length of P-wave (MVP score) was calculated. New-onset diagnoses of AF were obtained from nation-wide registers. RESULTS: During follow up, 66 patients (7%) developed AF. After adjustment for age and gender, the independent predictors of AF were abnormal P-wave axis > 75° (HR 1.63 CI95% 1.95-11.03) and MVP score 4 (HR 6.17 CI 95% 1.76-21.64), both correlated with LA area: Person r - 0.146, p < 0.001 and 0.192, p < 0.001 respectively. Advanced IAB (aIAB) with biphasic P-wave morphology in leads III and aVF was the most prevalent variant of aIAB and predicted AF in a univariate model (HR 2.59 CI 95% 1.02-6.58). CONCLUSION: P-wave frontal axis and MVP score are ECG-based AF predictors in the population-based cohort. Our study provides estimates for prevalence and prognostic importance of different variants of aIAB, providing a support to use biphasic P-wave morphology in lead aVF as the basis for aIAB definition.

Can 24 h of ambulatory ECG be used to triage patients to extended monitoring?

BACKGROUND: Access to long-term ambulatory recording to detect atrial fibrillation (AF) is limited for economical and practical reasons. We aimed to determine whether 24 h ECG (24hECG) data can predict AF detection on extended cardiac monitoring. METHODS: We included all US patients from 2020, aged 17-100 years, who were monitored for 2-30 days using the PocketECG device (MEDICALgorithmics), without AF ≥30 s on the first day (n = 18,220, mean age 64.4 years, 42.4% male). The population was randomly split into equal training and testing datasets. A Lasso model was used to predict AF episodes ≥30 s occurring on days 2-30. RESULTS: The final model included maximum heart rate, number of premature atrial complexes (PACs), fastest rate during PAC couplets and triplets, fastest rate during premature ventricular couplets and number of ventricular tachycardia runs ≥4 beats, and had good discrimination (ROC statistic 0.7497, 95% CI 0.7336-0.7659) in the testing dataset. Inclusion of age and sex did not improve discrimination. A model based only on age and sex had substantially poorer discrimination, ROC statistic 0.6542 (95% CI 0.6364-0.6720). The prevalence of observed AF in the testing dataset increased by quintile of predicted risk: 0.4% in Q1, 2.7% in Q2, 6.2% in Q3, 11.4% in Q4, and 15.9% in Q5. In Q1, the negative predictive value for AF was 99.6%. CONCLUSION: By using 24hECG data, long-term monitoring for AF can safely be avoided in 20% of an unselected patient population whereas an overall risk of 9% in the remaining 80% of the population warrants repeated or extended monitoring.

Markers of Atrial Myopathy in the General Population: Prevalence, Predictors, and Inter-Relations.

BACKGROUND: Atrial myopathy refers to structural and functional cardiac abnormalities associated with atrial fibrillation and stroke, but appropriate diagnostic criteria are lacking. OBJECTIVES: This study aimed to assess prevalence, clinical correlates, and overlap between potential atrial myopathy markers. METHODS: The population-based SCAPIS (Swedish CArdioPulmonary bioImage Study) prospectively included 6,013 subjects without atrial fibrillation with 24-hour electrocardiograms. Resting electrocardiograms measuring P-wave indices were collected at 1 screening site (n = 1,201), and a random sample (n = 385) had echocardiographic left atrial volume index (LAVi). Atrial myopathy markers were defined as ≥500 premature atrial complexes/24 h, LAVi ≥34 mL/m2, P-wave duration >120 milliseconds, or P-wave terminal force in V1 >4,000 ms·s. Clinical correlates included age, sex, body mass index, height, smoking, physical activity, coronary artery disease, diabetes, systolic blood pressure, antihypertensive medication, and low education. RESULTS: Atrial myopathy was common; 42% of the sample with all diagnostic modalities available had ≥1 atrial myopathy marker, but only 9% had 2 and 0.3% had ≥3. Only P-wave duration and LAVi were correlated (ρ = 0.10; P = 0.04). Clinical correlates of premature atrial complexes, P-wave indices, and LAVi differed; current smoking (34% increase; P < 0.001), systolic blood pressure (4%/mm Hg increase; P = 0.01), diabetes (35% increase; P = 0.001), and coronary artery disease (71% increase; P = 0.003) were associated with premature atrial complexes, physical activity ≥2 h/wk was associated with increased LAVi (ß-coefficient = 3.1; P < 0.0001) and body mass index was associated with P-wave duration (ß-coefficient = 0.4/kg/m2; P < 0.0001). CONCLUSIONS: In the general population, indirect markers of atrial myopathy are common but only weakly correlated, and their risk factor patterns are different. More studies are needed to accurately identify individuals with atrial myopathy with diagnostic methods.

Ventricular tachycardia risk prediction with an abbreviated duration mobile cardiac telemetry.

Background: Ventricular tachycardia (VT) occurs intermittently, unpredictably, and has potentially lethal consequences. Objective: Our aim was to derive a risk prediction model for VT episodes ≥10 beats detected on 30-day mobile cardiac telemetry based on the first 24 hours of the recording. Methods: We included patients who were monitored for 2 to 30 days in the United States using full-disclosure mobile cardiac telemetry, without any VT episode ≥10 beats on the first full recording day. An elastic net prediction model was derived for the outcome of VT ≥10 beats on monitoring days 2 to 30. Potential predictors included age, sex, and electrocardiographic data from the first 24 hours: heart rate; premature atrial and ventricular complexes occurring as singlets, couplets, triplets, and runs; and the fastest rate for each event. The population was randomly split into training (70%) and testing (30%) samples. Results: In a population of 19,781 patients (mean age 65.3 ± 17.1 years, 43.5% men), with a median recording time of 18.6 ± 9.6 days, 1510 patients had at least 1 VT ≥10 beats. The prediction model had good discrimination in the testing sample (area under the receiver-operating characteristic curve 0.7584, 95% confidence interval 0.7340-0.7829). A model excluding age and sex had an equally good discrimination (area under the receiver-operating characteristic curve 0.7579, 95% confidence interval 0.7332-0.7825). In the top quintile of the score, more than 1 in 5 patients had a VT ≥10 beats, while the bottom quintile had a 98.2% negative predictive value. Conclusion: Our model can predict risk of VT ≥10 beats in the near term using variables derived from 24-hour electrocardiography, and could be used to triage patients to extended monitoring.

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic.

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

Elevated premature ventricular complex counts on 24-hour electrocardiogram predict incident atrial fibrillation and heart failure-A prospective population-based cohort study.

Background: Premature ventricular complexes (PVCs) are known to predict heart failure (HF) and premature atrial contractions (PACs) are known to predict atrial fibrillation (AF) and stroke. PVCs and PACs share pathophysiological mechanisms; however, the combined effects of PVCs and PACs on HF, AF, and stroke risk have not been studied. Objectives: To study elevated PVC counts on 24-hour electrocardiogram monitoring (24hECG) in relation to incidence of AF, HF, and stroke, and whether this effect is altered by PAC frequency. Methods: The prospective population-based Malmö Diet and Cancer study includes 24hECG registrations in 375 AF- and HF-free subjects (mean age 65 years, 55% women). During 17 years of follow-up there were 28 HF, 89 AF, and 28 stroke events. The hazard ratios (HR) of elevated PVC counts (defined as the top quartile, ≥77/24 hours) vs lower quartiles were assessed using multivariable adjusted Cox regression models. Results: Elevated PVC counts predicted incident AF (HR 1.9, 95% confidence interval [CI] 1.2-3.0) and HF (HR 3.1, 95% CI 1.4-7.0). Results were similar after adjustment for NT-proBNP and PACs. Multiform PVCs were associated with even higher risks (HR 2.8, 95% CI: 1.7-4.6 for AF; HR 5.0, 95% CI 2.2-11.7 for HF), as was the presence of both elevated PACs and PVCs (9% of the population, HR 4.1, 95% CI 2.4-6.8 for AF and HR 4.3, 95% CI 1.7-11.4 for HF). No significant association was found between elevated PVC counts and incident stroke. Conclusion: Elevated PVC counts predict incident AF and HF, particularly if PVCs are multiform or occur in combination with elevated PAC counts.

Cardiovagal Function Measured by the Deep Breathing Test: Relationships With Coronary Atherosclerosis.

Background The cardiovagal function can be assessed by quantification of respiratory sinus arrhythmia (RSA) during a deep breathing test. However, population studies of RSA and coronary atherosclerosis are lacking. This population-based study examined the relationship between RSA during deep breathing and coronary atherosclerosis, assessed by coronary artery calcium score (CACS). Methods and Results SCAPIS (Swedish Cardiopulmonary Bioimage Study) randomly invited men and women aged 50 to 64 years from the general population. CACS was obtained from computed tomography scanning, and deep breathing tests were performed in 4654 individuals. Expiration-inspiration differences (E-Is) of heart rates were calculated, and reduced RSA was defined as E-I in the lowest decile of the population. The relationship between reduced RSA and CACS (CACS≥100 or CACS≥300) was calculated using multivariable-adjusted logistic regression. The proportion of CACS≥100 was 24% in the lowest decile of E-I and 12% in individuals with E-I above the lowest decile (P<0.001), and the proportion of CACS≥300 was 12% and 4.8%, respectively (P<0.001). The adjusted odds ratio (OR) for CACS≥100 was 1.42 (95% CI, 1.10-1.84) and the adjusted OR for CACS≥300 was 1.62 (95% CI, 1.15-2.28), when comparing the lowest E-I decile with deciles 2 to 10. Adjusted ORs per 1 SD lower E-I were 1.17 (P=0.001) for CACS≥100 and 1.28 (P=0.001) for CACS≥300. Conclusions Low RSA during deep breathing is associated with increased coronary atherosclerosis as assessed by CACS, independently of traditional cardiovascular risk factors. Cardiovagal dysfunction could be a prevalent and modifiable risk factor for coronary atherosclerosis in the general population.

Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration.

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia.

LVS-HARMED Risk Score for Incident Heart Failure in Patients With Atrial Fibrillation Who Present to the Emergency Department: Data from a World-Wide Registry.

Background Heart failure (HF) is a common complication to atrial fibrillation (AF), leading to rehospitalization and death. Early identification of patients with AF at risk for HF might improve outcomes. We aimed to derive a score to predict 1-year risk of new-onset HF after an emergency department (ED) visit with AF. Methods and Results The RE-LY AF (Randomized Evaluation of Long-Term Anticoagulant Therapy) registry enrolled patients with AF presenting to an ED in 47 countries, and followed them for a year. The end point was HF hospitalization and/or HF death. Among 15 400 ED patients, 9765 had no prior HF (mean age, 64.9±14.9 years). Within 1 year, new-onset HF developed in 6.8% of patients, of whom 21% died of HF. Independent predictors of HF included left ventricular hypertrophy (odds ratio [OR], 1.47; 95% CI, 1.19-1.82), valvular heart disease (OR, 1.55; 95% CI, 1.18-2.04), smoking (OR, 1.42; 95% CI, 1.12-1.78), height (OR, 0.93; 95% CI, 0.90-0.95 per 3 cm), age (OR, 1.11; 95% CI, 1.07-1.15 per 5 years), rheumatic heart disease (OR, 1.77, 95% CI, 1.24-2.51), prior myocardial infarction (OR, 1.85; 95% CI, 1.45-2.36), remaining in AF at ED discharge (OR, 1.86; 95% CI, 1.46-2.36), and diabetes (OR, 1.33; 95% CI, 1.09-1.64). A continuous risk prediction score (LVS-HARMED [left ventricular, valvular heart disease, smoking or other tobacco use, height, age, rheumatic heart disease, myocardial infarction, emergency department discharge rhythm, and diabetes]) had good discrimination (C statistic, 0.735; 95% CI, 0.716-0.755). Validation was conducted internally using bootstrapping (optimism-corrected C statistic, 0.705) and externally (C statistic, 0.699). The 1-year incidence of HF hospitalization and/or HF death across quartile groups of the score was 1.1%, 4.5%, 6.9%, and 14.4%, respectively. LVS-HARMED also predicted incident stroke (C statistic, 0.753; 95% CI, 0.728-0.778). Conclusions The LVS-HARMED score predicts new-onset HF after an ED visit for AF. Preventative strategies should be considered in patients with high LVS-HARMED HF risk.

Sodium-Glucose Co-Transporter Inhibitors and Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66-0.86]; I2=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57-0.85]; I2=0%)-similar to the effect estimate for patients without AF, P value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.

Heart rate and adverse outcomes in patients with prevalent atrial fibrillation.

OBJECTIVE: The optimal target heart rate in patients with prevalent atrial fibrillation (AF) is not well defined. The aim of this study was to analyse the associations between heart rate and adverse outcomes in a large contemporary cohort of patients with prevalent AF. METHODS: From two prospective cohort studies, we included stable AF outpatients who were in AF on the baseline ECG. The main outcome events assessed during prospective follow-up were heart failure hospitalisation, stroke or systemic embolism and death. The associations between heart rate and adverse outcomes were evaluated using multivariable Cox regression models. RESULTS: The study population consisted of 1679 patients who had prevalent AF at baseline. Mean age was 74 years, and 24.6% were women. The mean heart rate on the baseline ECG was 78 (±19) beats per minute (bpm). The median follow-up was 3.9 years (IQR 2.2-5.0). Heart rate was not significantly associated with heart failure hospitalisation (adjusted HR (aHR) per 10 bpm increase, 1.00, 95% CI 0.94 to 1.07, p=0.95), stroke or systemic embolism (aHR 0.95, 95% CI 0.84 to 1.07, p=0.38) or death (aHR 1.02, 95% CI 0.95 to 1.09, p=0.66). There was no evidence of a threshold effect for heart rates <60 bpm or >100 bpm. CONCLUSIONS: In this large contemporary cohort of outpatients with prevalent AF, we found no association between heart rate and adverse outcome events. These data are in line with recommendations that strict heart rate control is not needed in otherwise stable outpatients with AF.

Cardiovascular risk factors and autonomic indices in relation to fatal and non-fatal coronary events.

OBJECTIVE: Mortality caused by coronary artery disease has markedly decreased in recent years. However, a substantial proportion of patients suffering a coronary event (CE) die within the first day, most of them out of hospital. We aimed to investigate how established cardiovascular (CV) risk factors and CV autonomic indices associate with fatal versus non-fatal CEs in the population. METHODS: 33 057 individuals (mean age; 45.6 years; 10 773 women) free of coronary artery disease at baseline were included. Baseline examination, including assessment of traditional CV risk factors and autonomic indices such as heart rate and orthostatic reaction, was performed during 1974-1992, after which the subjects were monitored for incident CV disease. The Lunn-McNeil competing risks approach with a prespecified multivariable model was used to assess differences in risks for fatal and non-fatal CEs in relation to baseline CV risk factors. RESULTS: During follow-up period of 29.7 years, 5494 subjects (6.10/1000 person-years) had first CE; 1554 of these were fatal. Age, male gender, smoking, body mass index (BMI), blood pressure, pulse pressure and resting heart rate had stronger relationships with fatal CE than with non-fatal events. The effects of diabetes, serum cholesterol, antihypertensive treatment and orthostatic blood pressure responses were similar for fatal and non-fatal CE. CONCLUSIONS: Several cardiovascular risk factors, such as smoking, high BMI, blood pressure and high resting heart rate, were preferentially associated with fatal compared with non-fatal CEs. These observations may require special attention in the overall efforts to further reduce coronary artery disease mortality.

Supraventricular arrhythmia, N-terminal pro-brain natriuretic peptide and troponin T concentration in relation to incidence of atrial fibrillation: a prospective cohort study.

BACKGROUND: Frequent supraventricular arrhythmia is associated with increased incidence of atrial fibrillation. However, it is unknown whether the prognostic significance of supraventricular arrhythmia is modified by plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (TnT). This study examined the interrelationships between NT-proBNP, TnT levels and frequent supraventricular arrhythmia, and whether these biomarkers and a measure of frequent supraventricular arrhythmia could improve risk assessment for incidence of AF. METHODS: Supraventricular extrasystoles (SVEs) and supraventricular tachycardias were assessed from 24-h electrocardiograph recordings in 373 individuals initially without AF. Elevated NT-pro-BNP, TnT and SVEs was defined as a measurement in the top quartile of the study population distribution. Incident cases of AF were retrieved by linkage with the Swedish National Patient Register. RESULTS: During a mean follow-up of 15.4 years, 88 subjects had a diagnosis of AF. After multivariable adjustment, individuals with both elevated NT-proBNP and frequent SVEs had a significantly increased incidence of AF, compared to subjects without elevated NT-proBNP or frequent SVEs (hazard ratio (HR) 4.61, 95% confidence interval (CI) 2.45-8.69), and compared to individuals with either elevated NT-proBNP or frequent SVEs (both P < 0.05). HRs for frequent SVEs alone or elevated NT-proBNP alone were 2.32 (95% CI 1.33-4.06) and 1.52 (95% CI 0.76-3.05), respectively. The addition of NT-pro-BNP and SVEs to a validated risk prediction score for AF, CHARGE-AF, resulted in improved prediction (Harrell's C 0.751 (95% CI 0.702-0.799) vs 0.720 (95% CI 0.669-0.771), P = 0.015). CONCLUSION: Subjects with both elevated NT-proBNP and frequent SVEs have substantially increased risk of AF, and the use of these variables could improve long-term prediction of incident AF.

Incidence and Predictors of Heart Failure in Patients With Atrial Fibrillation.

BACKGROUND: Heart failure (HF) is a frequent cause of hospitalization and death in patients with atrial fibrillation (AF). Identifying AF patients at risk of HF hospitalization could help select individuals for intensive follow-up and treatment. METHODS: We pooled data from 3 randomized trials (ACTIVE-A, RE-LY, AVERROES) of AF patients, for derivation and internal validation of a risk score for first HF hospitalization. Secondary endpoints were cardiovascular death and a composite of HF hospitalizations and cardiovascular death. RESULTS: In 23,503 patients, the mean age was 71.3 years, and 62% were male. Over a mean follow-up of 2.0 years, 875 patients (3.7%) experienced their first HF hospitalization, and 1037 patients (4.4%) died from cardiovascular causes. Incidence rates per 100 patient-years were 1.85 for HF hospitalizations, 2.15 for cardiovascular death, and 3.71 for the composite. Independent predictors for HF hospitalizations included the following: increased age, weight, heart rate and serum creatinine level, lower height and systolic blood pressure, diabetes, vascular disease, valvular disease, heart rhythm, left ventricular hypertrophy, and intraventricular conduction delay. The C-statistic (95% confidence intervals by bootstrap simulations) was 0.717 (0.705-0.732). At 2 years of follow-up, the incidence rate of the primary outcome increased across risk-score quintiles: 0.49, 0.87, 1.29, 2.44, and 4.51 per 100 patient-years, respectively. Patients in the highest quintile had an absolute risk of 6.8% for the primary endpoint at 2 years. CONCLUSIONS: In a large AF population, new-onset HF was common. A combination of characteristics can identify high-risk patients for whom strategies to prevent HF should be considered.

INTRODUCTION: L'insuffisance cardiaque (IC) est une cause fréquente d'hospitalisation et de décès chez les patients atteints de fibrillation auriculaire (FA). Le repérage des patients atteints de FA exposés au risque d'hospitalisation liée à l'IC pourrait faciliter la sélection des individus pour un suivi et un traitement intensifs. MÉTHODES: Nous avons regroupé les données de trois essais contrôlés (ACTIVE-A, RE-LY, AVERROES) de patients atteints de FA pour obtenir la dérivation et la validation interne d'un score de risque lors de la première hospitalisation liée à l'IC. Les critères secondaires étaient les décès dus aux maladies cardiovasculaires et le critère composite d'hospitalisations liées à l'IC et de décès dus aux maladies cardiovasculaires. RÉSULTATS: L'âge moyen des 23 503 patients, dont 62 % étaient des hommes, était de 71,3 ans. Durant un suivi moyen de 2,0 ans, 875 patients (3,7 %) ont subi leur première hospitalisation liée à l'IC, et 1 037 patients (4,4 %) sont morts de maladies cardiovasculaires. Les taux d'incidence par 100 patients-années étaient de 1,85 pour les hospitalisations liées à l'IC, de 2,15 pour les décès dus aux maladies cardiovasculaires et de 3,71 pour le critère composite. Les prédicteurs indépendants des hospitalisations liées à l'IC étaient les suivants : l'âge avancé, le poids, la fréquence cardiaque et la concentration sérique de la créatinine, la taille inférieure et la pression artérielle systolique, le diabète, les maladies vasculaires, la valvulopathie, le rythme cardiaque, l'hypertrophie ventriculaire gauche et le retard de conduction intraventriculaire. La statistique C (intervalles de confiance à 95 % obtenus par simulations d'auto-amorçage) était de 0,717 (0,705-0,732). Après deux ans de suivi, le taux d'incidence du critère d'évaluation principal augmentait de façon respective dans tous les quintiles de scores de risque : 0,49, 0,87, 1,29, 2,44 et 4,51 par 100 patients-années. Les patients dans le quintile supérieur avaient un risque absolu du critère d'évaluation principal de 6,8 % après deux ans. CONCLUSIONS: Dans une vaste population atteinte de FA, l'IC d'apparition récente était fréquente. La combinaison des caractéristiques peut permettre de déterminer les patients exposés à un risque élevé chez lesquels des stratégies de prévention de l'IC devraient être envisagées.

Modifiable risk factors predict incident atrial fibrillation and heart failure.

OBJECTIVE: Heart failure (HF) frequently complicates atrial fibrillation (AF) and significantly increases mortality risk. Limited data exist on the modifiable risk factors associated with development of HF in AF patients. METHODS: We examined two large, prospective, population-based cohorts without prior AF or HF at baseline: Malmö Preventive Project (MPP, n=32 625) and Malmö Diet and Cancer Study (MDCS, n=27 695). Using Lunn-McNeil competing risks, multivariable Cox models were constructed to determine hazard ratios (HR) and 95% confidence intervals (CI) of risk factors for incident HF with AF, and AF alone. RESULTS: Mean follow-up in MPP and MDCS was 27.6±8.4 and 17.7±5.3 years. In MPP, body mass index (HR 1.11, 95% CI 1.09 to 1.13 vs HR 1.05, 95% CI 1.04 to 1.06 per kg/m2), systolic blood pressure (HR 1.20, 95% CI 1.24 to 1.26 vs HR 1.08, 95% CI 1.06 to 1.10 per 10 mm Hg) and current cigarette smoking (HR 1.73, 95% CI 1.54 to 1.95 vs HR 1.23, 95% CI 1.15 to 1.32) had stronger associations with incident AF with HF compared with AF alone (all p for difference <0.0001). Similar results were observed in MDCS (all p for difference <0.009). These three risk factors and diabetes accounted for 51.8% and 54.1% of the population attributable risk (PAR) for AF with HF in MPP and MDCS, respectively, compared with 20.1% and 27.0% for AF alone. CONCLUSIONS: Obesity, hypertension and active smoking preferentially associated with AF with HF, compared with AF alone, and accounted for >50% of the PAR. Randomised trials are needed to assess whether risk factor modification can reduce the incidence of AF with HF and reduce mortality.

Heart rate and premature atrial contractions at 24hECG independently predict atrial fibrillation in a population-based study.

BACKGROUND: Low resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats. OBJECTIVE: To study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort. METHODS: In the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance. RESULTS: There were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001). CONCLUSION: Low mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Searching for Atrial Fibrillation Poststroke: A White Paper of the AF-SCREEN International Collaboration.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Increased vascular endothelial growth factor D is associated with atrial fibrillation and ischaemic stroke.

OBJECTIVE: Vascular endothelial growth factor D (VEGF-D) has important functions in lymphangiogenesis and angiogenesis. High plasma levels of VEGF-D have been associated with incidence of heart failure. The association of VEGF-D with atrial fibrillation (AF) and stroke is unclear and we hypothesised that VEGF-D could also be associated with incidence of AF and ischaemic stroke. METHODS: VEGF-D was measured in fasting blood samples of 4689 subjects (40% men) without a history of AF from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Median age was 58 years (range 46-68). Cox regression analyses, adjusted for multiple risk factors, was used to assess AF and ischaemic stroke risk in relation to VEGF-D levels. RESULTS: During a median follow-up time of 20.6 years, there were 637 cases of incident AF and 322 cases of first ischaemic stroke. After adjustment, VEGF-D was significantly associated with AF (HR 1.13(95% CI 1.04 to 1.23) per 1 SD increase) and ischaemic stroke (HR 1.14(95% CI 1.02 to 1.28) per 1 SD). The association with ischaemic stroke was explained by an increased incidence of AF-related stroke. HRs per 1 SD were 1.34 (95% CI 1.04 to 1.71) for AF-related ischaemic stroke and 1.04 (95% CI 0.90 to 1.19) for ischaemic stroke without AF. CONCLUSIONS: Increased VEGF-D concentrations were associated with AF and ischaemic stroke. The relationship with ischaemic stroke was more pronounced in subjects with a diagnosis of AF.