Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism-the Find-AF 2 study-rationale and design.

BACKGROUND: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. METHODS: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. CONCLUSIONS: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care.

Higher troponin T serum concentrations in hospital patients without diagnosed cardiac diseases compared to a population-based cohort.

OBJECTIVES: Upper reference limits of high-sensitivity cardiac troponin T (hs-cTnT) are derived from healthy, population-based cohorts, and are frequently exceeded in hospitalized patients. In this study we aim to systematically examine the differences between in-hospital patients with no diagnosed cardiac diseases and a population-based cohort. METHODS: Retrospective analyses were performed in two independent cohorts. We included 5,652 participants of the prospective population-based LIFE cohort as well as 9,300 patients having been treated at our hospital between 2014 and 2021. In both cohorts, subjects with diagnosed or suspected cardiac diseases were excluded. We used Spearman's rank correlation for correlation analyses of hs-cTnT serum concentrations and age. Sex- and age-adjusted 99th percentiles for hs-cTnT in subjects with preserved renal function were obtained in both cohorts. RESULTS: In both cohorts, hs-cTnT serum concentrations positively correlated with age. Male sex was associated with higher hs-cTnT serum concentrations. Persons treated in hospital showed significantly higher hs-cTnT concentrations in females and males aged above 50. While in the population-based cohort only 99th percentile hs-cTnT results of females aged above 70 and males aged above 60 years exceeded the assay's upper reference limit, the 99th percentiles of in-hospital females over 40 years and males of all age groups exceeded this threshold. CONCLUSIONS: Besides age and sex, hospitalization per se is correlated with higher serum concentrations of hs-cTnT in most age groups. Our results indicate, that unconditionally applying current hs-cTnT cut-offs to inpatients might overestimate myocardial infarction and potentially lead to overdiagnosis.

Age-Dependent Detection of Atrial Fibrillation with Implantable Cardiac Monitors in Patients with Cryptogenic Stroke.

Background Continuous monitoring using implantable cardiac monitors (ICMs) results in atrial fibrillation (AF) detection rates of up to 30% in patients with cryptogenic stroke (CS). Although higher age is an independent risk factor for AF, there are no age-specific recommendations for the implantation of ICM. Objective The aim of this study was to analyze age-related AF rates in patients with CS and continuous rhythm monitoring, to determine the rates of oral anticoagulation (OAC) and recurrent cerebrovascular events (stroke or transient ischemic attack) in patients with ICM-detected AF, and to describe the temporal relationship of AF detection and recurrent cerebrovascular events. Methods In this observational study, patients with CS provided with ICMs were systematically followed. All patients underwent 72-hour electrocardiography monitoring, transcranial Doppler ultrasound, and transthoracic echocardiography prior to ICM insertion. Follow-up included a regular outpatient presentation every 3 months with medical history, physical examination, and interrogation of the ICM. Results One-hundred eighty-six patients (mean age: 65 ± 12 years, 54% female) were included in this analysis. AF was detected in 6, 27, 56, and 65% ( p < 0.001) of patients aged less than 60, 60 to 69, 70 to 79, and more than or equal to 80 years, respectively. All patients with AF under 60 years had an impaired left ventricular systolic function. OAC was initiated in 85% of the patients with AF. Recurrent cerebrovascular events occurred in 34 patients of whom 14 had a diagnosis of AF. In nine patients, AF was diagnosed before the occurrence of a recurrent cerebrovascular event. Conclusion AF prevalence increased with age and was absent in CS patients younger than 60 years and with preserved left ventricular ejection fraction. The temporal relationship of AF and recurrent cerebrovascular events was weak.

Signs of left atrial disease and 10-year risk of atrial fibrillation.

BACKGROUND: The contribution of left atrial disease and excessive supraventricular ectopic activity (ESVEA) to the risk for incident atrial fibrillation (AF) is incompletely understood. OBJECTIVE: To analyse the ten-year risk to develop AF in patients with cardiovascular risk factors and to define the impact of parameters of left atrial disease and ESVEA on AF risk. METHODS: 148 patients from the Diast-CHF trial with at least one cardiovascular risk factor and free of AF at baseline were followed for 10 years. Left atrial disease was defined as left atrial volume index (LAVI) >35 ml/m2, P-terminal force in lead V1 (PTFV1) >4000 ms*µV or elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/ml. We analyzed the association of these parameters and ESVEA (either >720 premature atrial contractions (PAC) or one atrial run >20 beats per day) on AF-free survival. RESULTS: After ten years, AF was newly detected in twelve patients (13.4%) with signs of left atrial disease and two patients (3.4%) without signs of left atrial disease (p = 0.04). LAVI (p = 0.005), ESVEA (p = 0.016) and NT-proBNP (p = 0.010) were significantly associated with AF-free survival in univariate analysis. A combined Cox model of left atrial disease parameters showed associations for NT-proBNP (HR 3.56; 95%CI 1.33-5.31; p = 0.04) and PAC (HR 2.66; 95%CI 1.25-10.15; p = 0.01) but not for LAVI or PTFV1 with AF-free survival. CONCLUSION: The risk for AF is higher in patients with cardiovascular risk factors and signs of left atrial disease. NT-proBNP and premature atrial contractions independently predict AF-free survival. The role of excessive supraventricular ectopic activity for the assessment of AF risk may be underestimated and requires further study.

Patients' attitude towards a sham-controlled trial on pulmonary vein isolation in atrial fibrillation.

BACKGROUND: The interpretation of recent trials on pulmonary vein ablation (PVI) for the treatment of atrial fibrillation (AF) is hampered by the lack of blinding and sham controls. The feasibility of a sham-controlled trial has been questioned. We aimed to assess the attitude of potential participants regarding a sham-controlled trial in a common AF-patient population planned for PVI. METHODS: Patients in two tertiary care centres planned for PVI were asked for their current AF symptoms using the Atrial Fibrillation Effect on QualiTy of Life (AFEQT) questionnaire 1 day before catheter ablation. Subsequently, the study design of a hypothetical sham-controlled PVI-study was introduced, and patients were asked for their agreement in participation. Telephone follow-up of the AFEQT questionnaire was conducted 3 months after PVI. RESULTS: One hundred and ninety-six patients (mean age 64 ± 11 years, 63% male) were included. Seventy-nine (40%) patients expressed their agreement to participate in the hypothetical sham-controlled trial. An additional 7% agreed to participate if a cross-over option after three months was offered. Agreement rate was similar in patients with first and Redo-PVI and minimal, moderate or severe symptoms. Mean overall AFEQT at baseline was 55 ± 19 and improved by 25 ± 20 points after 3 months (p < 0.001 versus baseline). CONCLUSION: With a participation rate of 40% in potential study participants, a sham-controlled trial for pulmonary vein isolation seems feasible. Patient-reported symptom relief after pulmonary vein isolation is in accordance with previous randomized open studies. The benefit of PVI should be rigorously evaluated in a sham-controlled trial.

Effect of remote ischemic preconditioning on electrophysiological parameters in nonvalvular paroxysmal atrial fibrillation: The RIPPAF Randomized Clinical Trial.

BACKGROUND: Atrial fibrillation (AF) remains the most relevant arrhythmia with a prevalence of 2%. The treatment options are either highly invasive and cost-intensive or limited by potential side effects or insufficient efficacy. However, no direct means of prevention that could reduce the burden of AF have been tested. OBJECTIVE: The purpose of this study was to determine whether remote ischemic preconditioning (RIPC) has an impact on inducibility and sustainability of AF. METHODS: A total of 146 patients with paroxysmal AF undergoing electrophysiology study were randomized to receive either RIPC, performed by short episodes of forearm ischemia, or sham intervention (clinicaltrials.gov identifier: NCT02779660). Effective refractory periods, conduction times, velocities, and conduction delays measured were analyzed by pacing from the coronary sinus (CS). End points of the study were the inducibility and sustainability of AF after prespecified rapid pacing sequences. RESULTS: RIPC significantly reduces the inducibility (odds ratio 0.35; 95% confidence interval 0.17-0.71; P = .003) and sustainability (odds ratio 0.36; 95% confidence interval 0.16-0.81; P = .01) of AF. Furthermore, it decreased dispersion of atrial refractory periods (16.0 ± 14.0 ms vs 22.7 ± 19.0 ms; P = .021) as well as atrial conduction delays (49.2 ± 19.6 ms vs 56.2 ± 22.5 ms; P = .049 for proximal CS and 42.4 ± 16.6 ms vs 49.8 ± 22.2 ms; P = .029 for distal CS). In the whole cohort, longer atrial conduction delay (57.6 ± 22.2 ms vs 50.0 ± 20.5 ms; P = .044) and slower conduction velocity (1.74 ± 0.3 mm/ms vs 1.93 ± 0.5 mm/ms; P = .006) were associated with inducibility of AF whereas a wider dispersion of effective refractory periods (25.9 ± 18.3 ms vs 15.7 ± 11.6 ms; P = .028) maintained AF episodes. CONCLUSION: RIPC reduces the inducibility and sustainability of AF, which is possibly mediated by changes in electrophysiological properties of the atria. It may be used as a simple noninvasive procedure to reduce AF burden.

Morphological determinators of platelet activation status in patients with atrial fibrillation.

BACKGROUND: Stage of platelet activation is an important modulator of stroke risk associated with atrial fibrillation (AF). However, factors determining such activation status of thrombocytes in patients with AF are still not well studied. METHODS AND RESULTS: We enrolled 83 patients (mean age 61 ±â€¯10 years, 61% male, mean CHA2DS2-VASc 2.1 ±â€¯1.4) with paroxysmal (75%) or persistent (25%) AF admitted for catheter ablation. Blood samples were collected directly from the left atrium (LA) and platelet activation status was measured by means of flow cytometric assessment in whole blood and light transmission aggregometry (LTA) in unstimulated and Thrombin-receptor-activated-peptide-6 (TRAP-6)-stimulated platelet rich plasma. In flow cytometry, we measured fractions of platelet microparticles and aggregates as well as P-selectin expression on platelets' surfaces. LTA findings are expressed as maximal aggregation (MA), primary slope (PS) and area under curve (AUC). Cardiac anatomy has been assessed by means of echocardiography and magnetic resonance imaging. Left atrial appendage (LAA) volume, but not LAA morphology nor morphological and functional parameters describing LA, was significantly correlated with increased pre-activation of platelets (R = 0.224, p = 0.043) and consecutive reduced response to TRAP-6 (R = 0.231, p = 0.037) measured by P-selectin expression in flow cytometry. Similarly, a reduced response to TRAP-6 in patients with larger LAA volume (PS: R = -0.240; p = 0.042; AUC: R = -0.244; p = 0.035; MA: R = -0.270; p = 0.019) as well as with heart failure (PS 54.75 vs 71.45, p = 0.026) was observed in LTA. CONCLUSION: In patients with AF, LAA volume correlates with extent of platelet activation status, this effect is aggravated in patients with heart failure.

Effect of remote ischemic preconditioning on electrophysiological and biomolecular parameters in nonvalvular paroxysmal atrial fibrillation (RIPPAF study): Rationale and study design of a randomized, controlled clinical trial.

Remote ischemic preconditioning (RIPC) has been studied in models of different cardiovascular entities. Recently, a beneficial effect of RIPC on incidence of atrial fibrillation (AF) in postsurgical patients has been suggested. However, the potential impact of RIPC on electrophysiological- and thrombogenesis-related parameters in the setting of paroxysmal nonvalvular AF has not been investigated. The aim of the study is to answer the following questions: (1) Does RIPC have impact on inducibility of AF in patients with known paroxysmal AF? If yes, what are the direct electrophysiological mechanisms of this phenomenon, and could RIPC be implemented to reduce AF burden? (2) Does RIPC have the potential to minimize thrombogenic effects of simulated episodes of AF? If so, what are inhibited components of thrombogenesis and can this be used to reduce thromboembolic risk related to paroxysmal AF? The presented study is a 2-arm, randomized, placebo-controlled, double-blinded, single-center trial in a cohort of 146 patients with paroxysmal AF referred for AF ablation in sinus rhythm. The study will collect electrophysiological data such as variability of P-wave morphology, atrial refractory period, conduction times, and inducibility/sustainability of AF. Furthermore, AF-induced prothrombotic processes will be analyzed by quantification of platelet aggregates, analysis of platelet function, and measurement of thrombogenesis-related plasma markers. Moreover, the study will provide a unique bio-database for further analysis of molecular and genetic mechanisms responsible for observed results.