Heart Failure Events After Long-term Continuous Screening for Atrial Fibrillation: Results From the Randomized LOOP Study.

BACKGROUND: Mounting evidence indicates that even device-detected subclinical atrial fibrillation is associated with a higher risk of heart failure (HF). However, the potential impact of atrial fibrillation screening on HF remains unknown. METHODS: The LOOP Study (Atrial Fibrillation detected by Continuous ECG Monitoring using Implantable Loop Recorder to prevent Stroke in High-risk Individuals) evaluated the effects of atrial fibrillation screening on stroke prevention using an implantable loop recorder (ILR) versus usual care in older individuals with additional stroke risk factors. In this secondary analysis, we explored the following HF end points: (1) HF event or cardiovascular death; (2) HF event; (3) event with HF with reduced ejection fraction (HFrEF); and (4) HFrEF event or cardiovascular death. Outcomes were assessed in a Cox model both as time-to-first events and as total (first and recurrent) events analyzed using the Andersen-and-Gill method. RESULTS: Of 6004 participants (mean age 74.7 and 52.7% men), 1501 were randomized to ILR screening and 4503 to the control group. In total, 77 (5.1%) in the ILR group versus 295 (6.6%) in the control group experienced the primary outcome of an HF event or cardiovascular death. Compared with usual care, ILR screening was associated with a nonsignificant reduction in the primary outcome for the time-to-first event analysis (hazard ratio, 0.78 [95% CI, 0.61-1.01]) and the total event analysis (hazard ratio, 0.77 [95% CI, 0.59-1.01]). Similar results were obtained for the HF event. A significant risk reduction in total events was observed in the ILR group for the composite of HFrEF event or cardiovascular death and for HFrEF event (hazard ratio, 0.74 [95% CI, 0.56-0.98] and 0.65 [95% CI, 0.44-0.97], respectively). CONCLUSIONS: In an older population with additional stroke risk factors, ILR screening for atrial fibrillation tended to be associated with a lower rate of total HF events and cardiovascular death, particularly those related to HFrEF. These findings should be considered hypothesis-generating and warrant further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.

Severe aortic stenosis treated with transcatheter aortic valve implantation or surgical aortic valve replacement with Perimount in Western Denmark 2016-2022: a nationwide retrospective study.

OBJECTIVES: The healthcare registries in Denmark present a unique opportunity to gain novel insights into the outcomes associated with both transcatheter and surgical approaches to aortic valve replacement. Our objective is to enhance shared decision-making by comparing long-term mortality and clinical outcomes between treatments. METHODS: This observational study included all patients with severe aortic stenosis undergoing elective isolated transfemoral transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) in Western Denmark between January 2016 and April 2022. Patient population and clinical data were identified from the Western Danish Heart Registry and the National Danish Patient Registry, respectively. A propensity score-matched population was generated. Outcomes were investigated according to Valve Academic Research Consortium-3. RESULTS: A total of 2269 TAVI patients and 1094 SAVR patients where identified. The propensity score-matched population consisted of 468 TAVI patients (mean[SD]age, 75.0[5.3] years) and 468 SAVR patients (mean[SD] age, 75.1[4.6]years). The Kaplan-Meier estimate for the 5-year all-cause mortality was 29.8% in the TAVI group and 16.9% for in the SAVR group (P = 0.019). The risk of all stroke or transient ischaemic attack after five year was 15.1% in the TAVI group and 11.0% in the SAVR group (P = 0.047). CONCLUSIONS: This study underscores the importance of evaluating all patient factors when choosing an aortic valve replacement method. Surgical aortic valve replacement was an excellent choice, especially for patients with New York Heart Association class I/II, ≥75 age, left ventricular ejection fraction ≥50%, or longer life expectancy.

Atorvastatin and the influence on postoperative atrial fibrillation after surgical aortic valve replacement (STARC) in adults at Odense University Hospital, Denmark: study protocol for a randomised controlled trial.

INTRODUCTION: Atrial fibrillation (AF) is the most common postoperative complication after surgical aortic valve replacement (SAVR) and occurs in up to 50% of the patients. Development of postoperative AF (POAF) is associated with a 2-3 fold increased risk of adverse events, including stroke, myocardial infarction and death.Several studies have implied that prophylactic Atorvastatin therapy could prevent POAF in patients undergoing coronary artery bypass graft. These studies suggest that Atorvastatin has rapid and significant pleiotropic actions that reduce the risk of POAF. However, prophylactic treatment with statins has yet to be understood in SAVR. The aim of this study is to investigate whether prophylactic administration of torvastatin reduces POAF in patients undergoing SAVR. METHODS AND ANALYSIS: In this investigator-initiated, prospective, parallel-group, randomised, double-blind, placebo-controlled single-centre trial, 266 patients undergoing elective solitary SAVR with bioprosthetic valve, with no prior history of AF, and statin-naïve will be randomised (1:1) to treatment with Atorvastatin (80 mg once daily) or matching placebo for 1-2 weeks prior to and 30 days after surgery. The primary endpoint is POAF defined as an episode of irregular RR-intervals without a traceable p-wave of at least 30 s duration. After discharge and until day 30 after surgery, POAF will be documented by either rhythm strip or 12-lead ECG. ETHICS AND DISSEMINATION: Protocol approval has been obtained from the Regional Scientific Ethical Committee for Southern Denmark (S-20210159), The Danish Medicines Agency (2021103821) and the Data Protection Agency (21/65621).The trial is conducted in accordance with the Declaration of Helsinki, the ICH-GCP (International Conference on Harmonisation Good Clinical Practice) guidelines and the legal regulations of Denmark. Study findings will be shared via peer-reviewed journal publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT05076019.

Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.

The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.

Potential role of conventional and speckle-tracking echocardiography in the screening of structural and functional cardiac abnormalities in elderly individuals: Baseline echocardiographic findings from the LOOP study.

BACKGROUND: Elderly individuals occupy an increasing part of the general population. Conventional and speckle-tracking transthoracic echocardiography may help guide risk stratification in these individuals. The purpose of this study was to evaluate the potential utility of conventional and speckle-tracking echocardiography in the screening of cardiac abnormalities in the elderly population. METHODS: Two cohorts of elderly individuals (sample size: 1441 and 944) were analyzed, who were part of a randomized controlled clinical trial (LOOP study) and of an observational study (Copenhagen City Heart Study), recruiting participants from the general population >70 years of age with cardiovascular risk factors (arterial hypertension, diabetes mellitus, heart failure, or prior stroke) and sinus rhythm. Participants underwent a comprehensive transthoracic echocardiographic examination, including myocardial speckle tracking. Cardiac abnormalities were defined according to the ASE/EACVI guidelines. RESULTS: Structural cardiac abnormalities such as left ventricular (LV) remodeling, mitral annular calcification (MAC), and aortic valve sclerosis (with or without stenosis) were highly prevalent in the LOOP study (40%, 39%, and 27%, respectively). Moreover, a high prevalence of functional cardiac alterations such as LV diastolic dysfunction (LVDD), abnormal LV longitudinal systolic strain (GLS), and abnormal left atrial (LA) reservoir strain was present in the LOOP study (27%, 18%, and 9%, respectively). Likewise, the rate of LVDD, abnormal GLS, and abnormal LA reservoir strain was comparable in the validation sample from the Copenhagen City Heart Study. In line with these findings, subjects with LV remodeling, MAC, and aortic valve changes had a higher prevalence of LVDD, abnormal GLS, and abnormal LA reservoir strain than those without structural cardiac alterations. CONCLUSION: The findings of this study highlight the potential clinical utility of conventional and speckle-tracking echocardiography in the screening of structural and functional cardiac abnormalities in the elderly population. Further studies are warranted to determine the prognostic relevance of these findings.

Association of Left Atrial Size Measured by Non-Contrast Computed Tomography with Cardiovascular Risk Factors-The Danish Cardiovascular Screening Trial (DANCAVAS).

Left atrium (LA) size is associated with adverse cardiovascular events. The purpose of this study was to investigate the association of LA enlargement measured by non-contrast CT (NCCT) with traditional cardiovascular risk factors. Individuals aged 60-75 years from the population-based multicentre Danish Cardiovascular Screening (DANCAVAS) trial were included in this cross-sectional study. The LA was manually traced on the NCCT scans, and the largest cross-section area was indexed to body surface area. All traditional risk factors were recorded, and a subgroup received an echocardiographic examination. We enrolled 14,987 individuals. Participants with known cardiovascular disease or lacking measurements of LA size or body surface area were excluded, resulting in 10,902 men for the main analysis and 616 women for a sensitivity analysis. Adjusted multivariable analysis showed a significantly increased indexed LA size by increasing age and pulse pressure, while smoking, HbA1c, and total cholesterol were associated with decreased indexed LA size. The findings were confirmed in a supplementary analysis including left ventricle ejection fraction and mass. In this population-based cohort of elderly men, an association was found between age and pulse pressure and increasing LA size. Surprisingly, smoking, HbA1c, and total cholesterol were associated with a decrease in LA size. This indicates that the pathophysiology behind atrial cardiomyopathy is not only reflected by enlargement, but also shrinking.

Accuracy, analysis time, and reproducibility of dedicated 4D echocardiographic left atrial volume quantification software.

Four-dimensional (4D) echocardiography may provide more accurate estimations of left atrial (LA) volumes than 2-dimensional (2D) measures. We sought to compare the concordance of a novel 4D LA quantification software versus 2D echocardiography against cardiac magnetic resonance (CMR). This was a multimodality imaging substudy of a randomized clinical trial (the LOOP study). Elderly participants with stroke risk factors were included. A subgroup of this study population underwent transthoracic echocardiography (n = 1441) and a subset underwent CMR within two weeks (n = 73). The mean age of the echocardiographic study population was 74 years and 54% were men. The maximal LA volume (LAVmax) was 47 mL by 2D, 52 mL by 4D, and 104 mL by CMR. While 2D echocardiography showed a moderate correlation with 4D (R2 = 0.51) it yielded significantly lower values for LAVmax with a mean difference of 4.5 ± 11.9 mL, p < 0.001. 4D echocardiography correlated strongly with CMR measurements (R2 = 0.70), whereas 2D echocardiography showed a moderate correlation (R2 = 0.53). However, both modalities systematically underestimated LAVmax largely compared to CMR (2D vs. CMR: - 54.9 ± 21.3 mL; 4D vs. CMR: - 49.7 ± 18.6 mL). Similar observations were made for minimal LA volume and LA volume before atrial contraction. Analyses time by 4D was shorter than for 2D (90 ± 11 vs. 118 ± 16 s, p < 0.001). Intra- and interobserver variability was lower for 4D than 2D. Four-dimensional echocardiography is faster, more reproducible, and correlates more closely to CMR than 2D echocardiography. Both 4D and 2D echocardiography systematically underestimates LA volumes compared to CMR, emphasizing that values of LA volumes are not interchangeable between echocardiography and CMR.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Effectiveness and safety of oral anticoagulation treatment beyond 1 year after venous thromboembolism in patients at intermediate recurrence risk.

Effectiveness and safety of long-term anticoagulation treatment are uncertain in venous thromboembolism (VTE) patients at intermediate risk of recurrence. We examined the association between treatment beyond 1 year and outcomes in a Danish nationwide register-based study. VTE patients at intermediate risk of recurrence, that is, non-cancer patients with a first-time unprovoked VTE, who started oral anticoagulation treatment within 30 days and were alive 365 days after the index VTE were included and followed between 2007 and 2015. Exposure was extended (>365 days) or intermediate (91-365 days) treatment. Analyses were done using Cox regression on a propensity score weighted population. We included 18 609 patients with 7232 (38.9%) receiving extended treatment. Mean duration of follow-up was 2.6 years. Compared with intermediate treatment, treatment beyond 365 days was associated with a lower weighted risk of recurrent VTE (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.49-0.65) and all-cause mortality (HR 0.81, 95% CI 0.72-0.90) and an increased risk of major bleeding (HR 1.87, 95% CI 1.58-2.22). In conclusion, extended anticoagulation treatment (predominantly warfarin) beyond 1 year was in real-life settings associated with a lower risk of recurrent VTE and all-cause mortality among VTE patients with an intermediate risk of recurrence. However, an increased bleeding risk should be considered.

Haematuria and urinary tract cancers in patients with atrial fibrillation treated with oral anticoagulants.

AIMS: Patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs) have an increased risk of bleeding including haematuria. In the general population, gross haematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross haematuria and urinary tract cancer in anticoagulated patients with AF. METHODS AND RESULTS: Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2015. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with and without gross haematuria. We included 125 063 AF patients with a median age of 74 years (interquartile range 65-80) and a majority of males (57%). The absolute risk of gross haematuria 12 months after treatment initiation increased with age ranging from 0.37% [95% confidence interval (CI) 0.31-0.42] to 0.85% (95% CI 0.75-0.96) in the youngest and oldest age groups of ≤70 and >80 years of age, respectively. The 1-year risk of urinary tract cancer after haematuria ranged from 4.2% (95% CI 2.6-6.6) to 6.5% (95% CI 4.6-9.0) for patients in age group >80 and 71-80 years, respectively. Gross haematuria conferred large risk ratios of urinary tract cancer when comparing patients with and without haematuria across all age groups. CONCLUSION: Gross haematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. These findings underline the importance of meticulously examining anticoagulated patients with haematuria.

Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder.

BACKGROUND: Stroke is an increasing health problem worldwide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention given to AF screening is rising, as new monitoring technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield. METHODS: Individuals with stroke risk factors but without AF were recruited from the general population to undergo screening with an implantable loop recorder. New-onset AF lasting ≥6 minutes was adjudicated by senior cardiologists. After continuous monitoring for >3 years, complete day-to-day heart rhythm data sets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value of screening with various simulated screening strategies compared with the implantable loop recorder. The diagnostic yield across strategies and population subgroups was compared by use of nonparametric tests. RESULTS: The rhythm data sets comprised 590 participants enduring a total of 659 758 days of continuous monitoring and 20 110 AF episodes. In these data, a single 10-second ECG yielded a sensitivity (and negative predictive value) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-second ECGs during 14 days and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-hour, 48-hour, 72-hour, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed or when the same monitoring duration was spread over several periods compared with a single period (eg, three 24-hour monitorings versus one 72-hour monitoring; P<0.0001 for all comparisons). The sensitivity was consistently higher among participants with age ≥75 years, male sex, CHADS2 score >2, or NT-proBNP (N-terminal pro-B-type natriuretic peptide) ≥40 pmol/L and among participants with underlying ≥24-hour AF episodes compared with shorter AF (P<0.0001 for all screening strategies). CONCLUSIONS: In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion, and number of screenings, although all strategies had low yield compared with the implantable loop recorder. The sensitivity was higher among participants who were older, were male, or had higher NT-proBNP. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.

Left atrial volume index and left ventricular global longitudinal strain predict new-onset atrial fibrillation in patients with transient ischemic attack.

This study aimed to investigate different echocardiographic parameters for predicting atrial fibrillation (AF) in patients with transient ischemic attack (TIA). Echocardiography was performed in 110 patients (median age 65.8 years, 53% males) with TIA and no history of stroke or AF. All patients underwent monitoring with ECG and 72 h Holter-monitoring, and if no AF was found, an insertable cardiac monitor (ICM) was implanted and patients were followed for a median of 2.2 years. AF was found in 14 patients: five with Holter-monitoring and nine with ICM. AF patients had significantly larger left atrial (LA) volumes indexes compared to patients without AF (26.7 vs. 33.7 ml/m2, P = 0.03 for 2D images and 26.5 vs. 33.5 ml/m2, P = 0.0008 for 3D images). Patients with AF also had depressed LA function assessed with LA emptying fraction measured with 2D echocardiography (46.3 vs. 57.3%, P = 0.005 for patients with and without AF, respectively). Patients with AF also had depressed left ventricular (LV) function compared to patients without AF. LV ejection fraction was 55 versus 61%, P = 0.04 in patients with and without AF, respectively. LV global longitudinal strain (absolute value) was 16.7 in patients with AF compared to 21.2 in patients without AF (P = 0.001). Echocardiographic measurements of LA and LV size and function can noninvasively predict AF in patients with TIA and could potentially be used to guide AF monitoring strategy.

The long-term efficacy of concomitant maze IV surgery in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and associated with increased risk of morbidity and mortality. AF surgery is widely used for rhythm control of AF, but previous studies have shown varying results. This study sought to investigate the long-term efficacy of concomitant maze IV (CMIV) surgery in an unselected AF population and identify predictors of late AF recurrence. METHODS: In total 144 consecutive patients, who underwent CMIV between January 2006 and December 2010 were enrolled. By data from electronic medical records, registers, and rhythm prints, late AF recurrences and heart rhythm at latest follow-up were retrospectively registered. All patients still alive were invited to an ambulant follow-up to update rhythm status. RESULTS: During a median (IQR) follow-up of 7.39 (2.67) years, 114 (79.2%) patients had recurrence. The cumulative incidence of sinus rhythm (SR) without antiarrhythmic drugs (AADs) was 52.3% after 1 year. Long-term results after 2, 5 and 7 years were 47.9%, 32.6% and 25.1%, respectively. At latest follow-up 34.7% were in SR off AADs. No difference in 10-year event-free survival stratified by recurrence were found (p = 0.678). Contrary, time to death (5.40 vs. 3.43 years, p = 0.004) revealed death as competing risk event. The Fine-Gray model identified preoperative sustained AF (SAF) (SHR 3.54, 95%CI [2.35;5.32], p < 0.001), AF duration (1.08, [1.05;1.11], p < 0.001), and postoperative atrial tachyarrhythmia (ATA) (2.29, [1.21;4.35], p = 0.011) as predictors. CONCLUSION: CMIV in the present cohort provided limited long-term success in obtaining SR. SAF, longer AF duration, and postoperative ATA were associated with late AF recurrence.

Measurement of left atrial volume by 2D and 3D non-contrast computed tomography compared with cardiac magnetic resonance imaging.

BACKGROUND: Cardiac magnetic resonance imaging (MRI) is considered the gold standard for assessment of left atrial (LA) volume. We assessed the feasibility of evaluating LA volume using 3D non-contrast computed tomography (NCCT). Furthermore, since manual tracing of LA volume is time consuming, we evaluated the accuracy of the LA area using 2D NCCT imaging for LA volume assessment. METHODS: MRI and NCCT imaging were performed in 69 patients before and one year after aortic valve replacement. In 3D MRI and 3D NCCT, each slice was manually traced, excluding the pulmonary veins and atrial appendage, and multiplied by slice spacing, thus generating a measure of LA volume. The LA volume was indexed to body surface area. On 2D NCCT, the largest axial cross-section LA area was traced manually. RESULTS: The mean LA volume was 102 ±â€¯28 ml in MRI compared with 103 ±â€¯28 ml in 3D NCCT. 3D NCCT showed good agreement with MRI measurements (mean difference -0.7 ml/m2; 95% confidence interval (CI) -2.2 to 0.9). By Bland-Altman, 3D NCCT also showed good agreement with MRI (limits of agreement: -18.7-17.4 ml/m2). Furthermore, good correlation was found between 2D NCCT and 3D NCCT LA volume (r = 0.93). CONCLUSION: 2D and 3D measurements of LA volume in non-contrast computed tomography are feasible and accurate.

Dabigatran reduces thrombin-induced platelet aggregation and activation in a dose-dependent manner.

Dabigatran is an oral anticoagulant and a reversible inhibitor of thrombin. Further, dabigatran might affect platelet function through a direct effect on platelet thrombin receptors. The aim was to investigate the effect of dabigatran on platelet activation and platelet aggregation. Healthy donor blood was incubated with dabigatran 0, 50, 500 ng/mL, corresponding to the therapeutic range of dabigatran peak plasma concentrations, and 10,000 ng/mL comprising a supra-therapeutic dabigatran plasma level. Platelet aggregation was tested with 96-well aggregometry. Flow cytometry was used to test platelet activation and platelet thrombin receptor expression (SPAN-12 and WEDE-15 expression). Agonists were thrombin, thrombin receptor-activating peptide, protease-activated receptor-4 agonist, collagen, collagen-related peptide, arachidonic acid, and adenosine diphosphate. All concentrations of dabigatran fully inhibited platelet aggregation for thrombin up to 2 IU/mL, while dabigatran did not affect platelet aggregation by other agonists. Platelet activation (percentage of platelets positive for activated GPIIb/IIIa, CD63, P-selectin) was reduced after thrombin stimulation in samples with dabigatran levels ≥500 ng/mL. After stimulation with thrombin, the percentage of activated GPIIb/IIIa-positive platelets was 99.8 ± 0.2% without dabigatran, 14.7 ± 4.7% with 500 ng/mL dabigatran, and 4.2 ± 0.2% with 10,000 ng/mL dabigatran, both p < 0.001 when compared to samples without dabigatran. Also, the receptor expression of GPIIb/IIIa, CD63, and P-selectin were reduced after dabigatran treatment. The expression of thrombin receptors was reduced at dabigatran on ≥ 500 ng/mL. In conclusion, dabigatran exclusively inhibits thrombin-induced platelet activation and aggregation with a dose-dependent response. Platelet stimulation with other agonists was not affected by dabigatran.

Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Does bipolar pacemaker current activate blood platelets?

OBJECTIVE: The aim of this study was to investigate whether bipolar pacemaker current lead can activate blood platelets. The null hypothesis was that 1 minute of electrical stimulation of platelets would not influence their subsequent reactivity to adenosine diphosphate (ADP). BACKGROUND: Both platelets and muscle cells contain actin and myosin filaments, and both cells are activated following calcium influx. Muscle cells open their calcium channels and contract when exposed to an electric current. Current through a bipolar pacemaker lead will expose a small volume of blood, including platelets, to the depolarizing current. Platelet activation may ensue, resulting in aggregation, release reaction, and contraction. In contrast, a unipolar pacemaker system will not depolarize blood, but transmit current directly into the myocardium, and the current afterward passes through other tissues before returning to the pacemaker can. METHODS: Platelet-rich plasma was prepared from two healthy subjects. Platelet reactivity to the agonist ADP was tested in paired samples in an aggregometer in a case/control setup. RESULTS: Eighteen of 46 tested pairs of platelet-rich plasma showed increased reactivity in the paced sample; 26 were unchanged while two showed decreased reactivity in the paced sample. Using a two-sided sign test, the null hypothesis was rejected (P = 0.0004). CONCLUSIONS: The study demonstrates increased reactivity to ADP in platelets exposed in vitro to stimulation by pacemaker current. The clinical relevance of these findings remains to be investigated.

Circadian profile of QT interval and QT interval variability in 172 healthy volunteers.

The limited prognostic value of QT dispersion has been demonstrated in recent studies. However, longitudinal data on physiological variations of QT interval and the influence of aging and sex are few. This analysis included 172 healthy subjects (89 women, 83 men; mean age 38.7 +/- 15 years). Beat-to-beat QT interval duration (QT, QTapex [QTa], Tend [Te]), variability (QTSD, QTaSD), and the mean R-R interval were determined from 24-hour ambulatory electrocardiograms after exclusion of artifacts and premature beats. All volunteers were fully active, awoke at approximately 7:00 AM, and had 6-8 hours of sleep. QT and R-R intervals revealed a characteristic day-night-pattern. Diurnal profiles of QT interval variability exhibited a significant increase in the morning hours (6-9 AM; P < 0.01) and a consecutive decline to baseline levels. In female subjects the R-R and Tend intervals were significantly lower at day- and nighttime. Aging was associated with an increase of QT interval mainly at daytime and a significant shift of the T wave apex towards the end of the T wave. The circadian profile of ventricular repolarization is strongly related to the mean R-R interval, however, there are significant alterations mainly at daytime with normal aging. Furthermore, the diurnal course of the QT interval variability strongly suggests that it is related to cardiac sympathetic activity and to the reported diurnal pattern of malignant ventricular arrhythmias.