In Silico Study of Local Electrical Impedance Measurements in the Atria - Towards Understanding and Quantifying Dependencies in Human

Background: Electrical impedance measurements have become an accepted tool for monitoring intracardiac radio frequency ablation. Recently, the long-established generator impedance was joined by novel local impedance measurement capabilities with all electrical circuit terminals being accommodated within the catheter. Objective: This work aims at in silico quantification of distinct influencing factors that have remained challenges due to the lack of ground truth knowledge and the superposition of effects in clinical settings. Methods: We introduced a highly detailed in silico model of two local impedance enabled catheters, namely IntellaNav MiFi™ OI and IntellaNav Stablepoint™, embedded in a series of clinically relevant environments. Assigning material and frequency specific conductivities and subsequently calculating the spread of the electrical field with the finite element method yielded in silico local impedances. The in silico model was validated by comparison to in vitro measurements of standardized sodium chloride solutions. We then investigated the effect of the withdrawal of the catheter into the transseptal sheath, catheter-tissue interaction, insertion of the catheter into pulmonary veins, and catheter irrigation. Results: All simulated setups were in line with in vitro experiments and in human measurements and gave detailed insight into determinants of local impedance changes as well as the relation between values measured with two different devices. Conclusion: The in silico environment proved to be capable of resembling clinical scenarios and quantifying local impedance changes. Significance: The tool can assists the interpretation of measurements in humans and has the potential to support future catheter development

Improving Clinical ECG-based Atrial Fibrosis Quantification With Neural Networks Through in silico P waves From an Extensive Virtual Patient Cohort

Fibrotic atrial cardiomyopathy is characterized by a replacement of healthy atrial tissue with diffuse patches exhibiting slow electrical conduction properties and altered myocardial tissue structure, which provides a substrate for the maintenance of reentrant activity during atrial fibrillation (AF). Therefore, an early detection of atrial fibrosis could be a valuable risk marker for new-onset AF episodes to select asymptomatic subjects for screening, allowing for timely intervention and optimizing therapy planning. We examined the potential of estimating the fibrotic tissue volume fraction in the atria based on P waves of the 12-lead ECG recorded in sinus rhythm in a quantitative and noninvasive way. Our dataset comprised 68,282 P waves from healthy subjects and 42,227 P waves from AF patients with low voltage areas in the atria, as well as 642,400 simulated P waves of a virtual cohort derived from statistical shape models with different extents of the left atrial myocardium replaced by fibrosis. The root mean squared error for estimating the left atrial fibrotic volume fraction on a clinical test set with a neural network trained on features extracted from simulated and clinical P waves was 16.57 %. Our study shows that the 12-lead ECG contains valuable information on atrial tissue structure. As such it could potentially be employed as an inexpensive and widely available tool to support AF risk stratification in clinical practic

Recent advances in the genetics of atrial fibrillation: from rare and common genetic variants to microRNA signaling

Besides traditional risk factors, atrial fibrillation (AF) also shares a strong genetic component. Here, we review the genetics of AF including monogenic forms of AF, heritability of AF, complex genetic risk of AF, and the role of microRNAs in AF pathophysiology. Thirtytwo mutations (17 genes) have been reported to cause familial AF. Mutations in cardiac ion channel genes or their subunits alter electrical properties and thereby lead to AF. Recently, also non-ion channel gene mutations have been identified to cause familial AF. Twin and community-based studies suggested AF to be heritable also on the population level. The AF risk in the offspring of an affected first-degree relative ranged between 2- to 5-fold, depending on the age of onset. Thereby, the risk of AF increases gradually the earlier the youngest relative of an AF patient developed the arrhythmia. African Americans bear a lesser risk of AF compared to individuals of European ancestry. Their risk rises with increasing European admixture. Genome wide association studies have revealed loci on chromosomes 4q25, 16q21 and 1q21 conferring risk of AF. Very recently, another consortial effort has identified a novel locus on chromosome 1, intronic to IL6R. IL6R encodes the a subunit of the interleukin 6 receptor. MicroRNAs were shown to regulate gene expression, and are increasingly reported to modify AF. A hallmark of AF pathophysiology is electrical and structural remodeling. MicroRNAs are involved in this process by regulating gene expression of cardiac ion channels, calcium handling proteins, transcription factors, and extracellular matrix related proteins

PROXIMITY TO COVID-19 ON MENTAL HEALTH SYMPTOMS AMONG HOSPITAL MEDICAL STAFF

Background: Exposure to patients with COVID-19 can have a significant impact on mental health of hospital medical staff. The aim of this study was to examine the influence of proximity to patients with COVID-19 considering occupational position and gender on the mental health of hospital staff. Subjects and methods: N=78 participants were included in the study, with n=40 of them with direct contact to patients with COVID-19 (51%); eight had contact with patients suspected of having COVID-19 (10%), and n=30 with no direct contact to people with COVID-19 (39%). Results: Multinomial regression analyses showed that proximity had a negative (inverse) influence on avoidance behaviour as part of PTSD, physical symptoms, somatization, compulsiveness and anger expression-in as tendency to suppress anger. In addition, there was a significant impact of the female gender on increased physical symptoms, while age, work experience and occupation had no further influence. Conclusions: These results that hospital medical staff is less psychologically stressed when closer to COVID-19 patients are inconsistent with previous studies. Self-efficacy and locus of control in these situations are relevant for processing the trauma. In summary, perception of personal risk is essential. Proximity is believed to be a proxy variable for personal risk perception. As a synopsis of these results, regular briefings of the hospital staff are recommended to prevent psychological impairment. They should contain specific information about conditions in the affected wards and the risk of infection, which could help reduce risk perception of medical personnel

PROXIMITY TO COVID-19 ON MENTAL HEALTH SYMPTOMS AMONG HOSPITAL MEDICAL STAFF

Background: Exposure to patients with COVID-19 can have a significant impact on mental health of hospital medical staff. The aim of this study was to examine the influence of proximity to patients with COVID-19 considering occupational position and gender on the mental health of hospital staff. Subjects and methods: N=78 participants were included in the study, with n=40 of them with direct contact to patients with COVID-19 (51%); eight had contact with patients suspected of having COVID-19 (10%), and n=30 with no direct contact to people with COVID-19 (39%). Results: Multinomial regression analyses showed that proximity had a negative (inverse) influence on avoidance behaviour as part of PTSD, physical symptoms, somatization, compulsiveness and anger expression-in as tendency to suppress anger. In addition, there was a significant impact of the female gender on increased physical symptoms, while age, work experience and occupation had no further influence. Conclusions: These results that hospital medical staff is less psychologically stressed when closer to COVID-19 patients are inconsistent with previous studies. Self-efficacy and locus of control in these situations are relevant for processing the trauma. In summary, perception of personal risk is essential. Proximity is believed to be a proxy variable for personal risk perception. As a synopsis of these results, regular briefings of the hospital staff are recommended to prevent psychological impairment. They should contain specific information about conditions in the affected wards and the risk of infection, which could help reduce risk perception of medical personnel

The INFluence of Remote monitoring on Anxiety/depRession, quality of lifE, and Device acceptance in ICD patients: a prospective, randomized, controlled, single-center trial.

Leppert F, Siebermair J, Wesemann U, et al. The INFluence of Remote monitoring on Anxiety/depRession, quality of lifE, and Device acceptance in ICD patients: a prospective, randomized, controlled, single-center trial. Clinical research in cardiology : official journal of the German Cardiac Society. 2020.BACKGROUND: Impact of telemedicine with remote patient monitoring (RPM) in implantable cardioverter-defibrillator (ICD) patients on clinical outcomes has been investigated in various clinical settings with divergent results. However, role of RPM on patient-reported-outcomes (PRO) is unclear. The INFRARED-ICD trial aimed to investigate the effect of RPM in addition to standard-of-care on PRO in a mixed ICD patient cohort.; METHODS AND RESULTS: Patients were randomized to RPM (n=92) or standard in-office-FU (n=88) serving as control group (CTL). At baseline and on a monthly basis over 1 year, study participants completed the EQ-5D questionnaire for the primary outcome Quality of Life (QoL), the Hospital Anxiety and Depression Scale, and the Florida Patient Acceptance Survey questionnaire for secondary outcomes. Demographic characteristics (82% men, mean age 62.3years) and PRO at baseline were not different between RPM and CTL. Primary outcome analysis showed that additional RPM was not superior to CTL with respect to QoL over 12months [+1.2 vs.+3.9 points in CTL and RPM group, respectively (p=0.24)]. Pre-specified analyses could not identify subgroups with improved QoL by the use of RPM. Neither levels of anxiety (-0.4 vs. -0.3, p=0.88), depression (+0.3 vs.±0.0, p=0.38), nor device acceptance (+1.1 vs.+1.6, p=0.20) were influenced by additional use of RPM.; CONCLUSION: The results of the present study show that PRO were not improved by RPM in addition to standard-of-care FU. Careful evaluation and planning of future trials in selected ICD patients are warranted before implementing RPM in routine practice

Stability of Circulating Blood-Based MicroRNAs - Pre-Analytic Methodological Considerations

Background and aim The potential of microRNAs (miRNA) as non-invasive diagnostic, prognostic, and predictive biomarkers, as well as therapeutic targets, has recently been recognized. Previous studies have highlighted the importance of consistency in the methodology used, but to our knowledge, no study has described the methodology of sample preparation and storage systematically with respect to miRNAs as blood biomarkers. The aim of this study was to investigate the stability of miRNAs in blood under various relevant clinical and research conditions: different collection tubes, storage at different temperatures, physical disturbance, as well as serial freeze-thaw cycles. Methods Blood samples were collected from 12 healthy donors into different collection tubes containing anticoagulants, including EDTA, citrate and lithium-heparin, as well as into serum collection tubes. MiRNA stability was evaluated by measuring expression changes of miR-1, miR21 and miR-29b at different conditions: varying processing time of whole blood (up to 72 hours (h)), long-term storage (9 months at -80 degrees C), physical disturbance (1 and 8 h), as well as in a series of freeze/thaw cycles (1 and 4 times). Results Different collection tubes revealed comparable concentrations of miR-1, miR-21 and miR-29b. Tubes with lithium-heparin were found unsuitable for miRNA quantification. MiRNA levels were stable for at least 24 h at room temperature in whole blood, while separated fractions did show alterations within 24 h. There were significant changes in the miR-21 and miR-29b levels after 72 h incubation of whole blood at room temperature (p< 0.01 for both). Both miR-1 and miR-21 showed decreased levels after physical disturbance for 8 h in separated plasma and miR-1 in serum whole blood, while after 1 h of disturbance no changes were observed. Storage of samples at -80 degrees C extended the miRNA stability remarkably, however, miRNA levels in long-term stored (9 months) whole blood samples were significantly changed, which is in contrast to the plasma samples, where miR-21 or miR-29b levels were found to be stable. Repetitive (n = 4) freeze-thaw cycles resulted in a significant reduction of miRNA concentration both in plasma and serum samples. Conclusion This study highlights the importance of proper and systematic sample collection and preparation when measuring circulating miRNAs, e.g., in context of clinical trials. We demonstrated that the type of collection tubes, preparation, handling and storage of samples should be standardized to avoid confounding variables influencing the results

Characterization of a porcine model of atrial arrhythmogenicity in the context of ischaemic heart failure

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-tohuman porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/ midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF

Risk for life-threatening arrhythmia in newly diagnosed peripartum cardiomyopathy with low ejection fraction: a German multi-centre analysis

Introduction Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy characterized by an acute reduction in left ventricular ejection fraction (LVEF). Sudden deaths during the course of PPCM are reported to be elevated, the underlying mechanisms remains unknown. The aim of the present multi-centre study was to evaluate the arrhythmia burden in a multi-centre approach in patients with PPCM using a wearable cardioverter/defibrillator (WCD). Methods and results Forty-nine patients from 16 German centres with newly diagnosed PPCM and LVEF <= 35% receiving a WCD were included in this retrospective analysis. Mean follow-up was 15 +/- 10 months. At diagnosis, mean age was 33 +/- 5 years, parity was 2.1 +/- 1.6, LVEF was 21 +/- 7%, NYHA functional class was 3.4 +/- 0.7. Mean wear time was 120 +/- 106 days, mean wear time per day was 21.4 +/- 3.3 h. Six (12%) patients presented eight ventricular tachyarrhythmias during WCD period: five episodes of VF, two sustained ventricular tachycardia (VT) and one non-sustained VT occurred. Conclusion This multicentre study underpins the elevated risk for ventricular tachyarrhythmias in patients with newly diagnosed PPCM and reduced LVEF. A WCD should be considered for 3-6 months in these patients to prevent sudden cardiac death from ventricular tachyarrhythmias

Apixaban versus PhenpRocoumon: Oral AntiCoagulation plus antiplatelet tHerapy in patients with Acute Coronary Syndrome and Atrial Fibrillation (APPROACH-ACS-AF)

Background A regimen of dual (DAT) vs. triple (TAT) antithrombotic therapy reduces bleeding in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, recent evidence suggests that DAT may be associated with an increased ischemic risk. This raises the question whether DAT rather than TAT should be recommended to AF patients that undergo PCI for acute coronary syndrome (ACS), carrying a particularly high risk of both bleeding and ischemic events, studied only as subgroups of previous trials. Methods and design The APPROACH-ACS-AF-(DZHK-7) trial is a multicenter prospective, randomized, open-label, blinded endpoint (PROBE) trial which will include patients presenting with an ACS managed by PCI and requiring oral anticoagulation (OAC) due to AF. The trial will test, whether a DAT-regimen comprising clopidogrel plus the non-Vitamin-K-antagonist oral anticoagulant (NOAC) apixaban is superior to a TAT-regimen of vitamin-K-antagonist (VKA) plus dual anti-platelet therapy (APT) with respect to bleeding. A total of 400 patients will be randomized 1:1 to a control-arm with guideline-recommended TAT with VKA plus clopidogrel and acetylsalicylic-acid and a study arm receiving DAT comprising apixaban plus clopidogrel. Patients will be followed-up for 6 months. The primary endpoint of the study is the cumulative incidence of BARC type ≥2 bleeding, secondary endpoints include a composite clinical ischemic outcome and net clinical outcome. Conclusions APPROACH-ACS-AF is the first trial dedicated to ACS patients, testing whether in terms of bleeding a DAT with NOAC is superior to a TAT regimen with VKA in high-risk ACS patients with AF