Ultra-High-Frequency ECG in Cardiac Pacing and Cardiac Resynchronization Therapy: From Technical Concept to Clinical Application.

Identifying electrical dyssynchrony is crucial for cardiac pacing and cardiac resynchronization therapy (CRT). The ultra-high-frequency electrocardiography (UHF-ECG) technique allows instantaneous dyssynchrony analyses with real-time visualization. This review explores the physiological background of higher frequencies in ventricular conduction and the translational evolution of UHF-ECG in cardiac pacing and CRT. Although high-frequency components were studied half a century ago, their exploration in the dyssynchrony context is rare. UHF-ECG records ECG signals from eight precordial leads over multiple beats in time. After initial conceptual studies, the implementation of an instant visualization of ventricular activation led to clinical implementation with minimal patient burden. UHF-ECG aids patient selection in biventricular CRT and evaluates ventricular activation during various forms of conduction system pacing (CSP). UHF-ECG ventricular electrical dyssynchrony has been associated with clinical outcomes in a large retrospective CRT cohort and has been used to study the electrophysiological differences between CSP methods, including His bundle pacing, left bundle branch (area) pacing, left ventricular septal pacing and conventional biventricular pacing. UHF-ECG can potentially be used to determine a tailored resynchronization approach (CRT through biventricular pacing or CSP) based on the electrical substrate (true LBBB vs. non-specified intraventricular conduction delay with more distal left ventricular conduction disease), for the optimization of CRT and holds promise beyond CRT for the risk stratification of ventricular arrhythmias.

Defining a metrologically traceable and sustainable calibration hierarchy of international normalized ratio for monitoring of vitamin K antagonist treatment in accordance with International Organization for Standardization (ISO) 17511:2020 standard: communication from the International Federation of Clinical Chemistry and Laboratory Medicine-SSC/ISTH working group on prothrombin time/international normalized ratio standardization.

Calibration of prothrombin time (PT) in terms of international normalized ratio (INR) has been outlined in "Guidelines for thromboplastins and plasmas used to control oral anticoagulant therapy" (World Health Organization, 2013). The international standard ISO 17511:2020 presents requirements for manufacturers of in vitro diagnostic (IVD) medical devices (MDs) for documenting the calibration hierarchy for a measured quantity in human samples using a specified IVD MD. The objective of this article is to define an unequivocal, metrologically traceable calibration hierarchy for the INR measured in plasma as well as in whole blood samples. Calibration of PT and INR for IVD MDs according to World Health Organization guidelines is similar to that in cases where there is a reference measurement procedure that defines the measurand for value assignment as described in ISO 17511:2020. We conclude that, for PT/INR standardization, the optimal calibration hierarchy includes a primary process to prepare an international reference reagent and measurement procedure that defines the measurand by a value assignment protocol conforming to clause 5.3 of ISO 17511:2020. A panel of freshly prepared human plasma samples from healthy adult individuals and patients on vitamin K antagonists is used as a commutable secondary calibrator as described in ISO 17511:2020. A sustainable metrologically traceable calibration hierarchy for INR should be based on an international protocol for value assignment with a single primary reference thromboplastin and the harmonized manual tilt tube technique for clotting time determination. The primary international reference thromboplastin reagent should be used only for calibration of successive batches of the secondary reference thromboplastin reagent.

Association of vectorcardiographic T-wave area with clinical and echocardiographic outcomes in cardiac resynchronization therapy.

AIMS: Data on repolarization parameters in cardiac resynchronization therapy (CRT) are scarce. We investigated the association of baseline T-wave area, with both clinical and echocardiographic outcomes of CRT in a large, multi-centre cohort of CRT recipients. Also, we evaluated the association between the baseline T-wave area and QRS area. METHODS AND RESULTS: In this retrospective study, 1355 consecutive CRT recipients were evaluated. Pre-implantation T-wave and QRS area were calculated from vectorcardiograms. Echocardiographic response was defined as a reduction of ≥15% in left ventricular end-systolic volume between 3 and 12 months after implantation. The clinical outcome was a combination of all-cause mortality, heart transplantation, and left ventricular assist device implantation. Left ventricular end-systolic volume reduction was largest in patients with QRS area ≥ 109 µVs and T-wave area ≥ 66 µVs compared with QRS area ≥ 109 µVs and T-wave area < 66 µVs (P = 0.004), QRS area < 109 µVs and T-wave area ≥ 66 µVs (P < 0.001) and QRS area < 109 µVs and T-wave area < 66 µVs (P < 0.001). Event-free survival rate was higher in the subgroup of patients with QRS area ≥ 109 µVs and T-wave area ≥ 66 µVs (n = 616, P < 0.001) and QRS area ≥ 109 µVs and T-wave area < 66 µVs (n = 100, P < 0.001) than the other subgroups. In the multivariate analysis, T-wave area remained associated with echocardiographic response (P = 0.008), but not with the clinical outcome (P = 0.143), when QRS area was included in the model. CONCLUSION: Baseline T-wave area has a significant association with both clinical and echocardiographic outcomes after CRT. The association of T-wave area with echocardiographic response is independent from QRS area; the association with clinical outcome, however, is not.

Left Bundle Branch Area Pacing and Atrioventricular Node Ablation in a Single-Procedure Approach for Elderly Patients with Symptomatic Atrial Fibrillation.

BACKGROUND: Implantation of a permanent pacemaker and atrioventricular (AV) node ablation (pace-and-ablate) is an established approach for rate and symptom control in elderly patients with symptomatic atrial fibrillation (AF). Left bundle branch area pacing (LBBAP) is a physiological pacing strategy that might overcome right ventricular pacing-induced dyssynchrony. In this study, the feasibility and safety of performing LBBAP and AV node ablation in a single procedure in the elderly was investigated. METHODS: Consecutive patients with symptomatic AF referred for pace-and-ablate underwent the treatment in a single procedure. Data on procedure-related complications and lead stability were collected at regular follow-up at one day, ten days and six weeks after the procedure and continued every six months thereafter. RESULTS: 25 patients (mean age 79.2 ± 4.2 years) were included and underwent successful LBBAP. In 22 (88%) patients, AV node ablation and LBBAP were performed in the same procedure. AV node ablation was postponed in two patients due to lead-stability concerns and in one patient on their own request. No complications related to the single-procedure approach were observed with no lead-stability issues at follow-up. CONCLUSIONS: LBBAP combined with AV node ablation in a single procedure is feasible and safe in elderly patients with symptomatic AF.

Interobserver Agreement on Intracranial Hemorrhage on Magnetic Resonance Imaging in Patients With Ischemic Stroke.

BACKGROUND: The Heidelberg Bleeding Classification, developed for computed tomography, is also frequently used to classify intracranial hemorrhage (ICH) on magnetic resonance imaging. Additionally, the presence of any ICH is frequently used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. We assessed the interobserver agreement on the presence of any ICH and the type of ICH according to the Heidelberg Bleeding Classification on magnetic resonance imaging in patients treated with reperfusion therapy. METHODS: We used 300 magnetic resonance imaging scans including susceptibility-weighted imaging or T2*-weighted gradient echo imaging of ischemic stroke patients within 1 week after reperfusion therapy. Six observers, blinded to clinical characteristics except for suspected location of the infarction, independently rated ICH according to the Heidelberg Bleeding Classification in random pairs. Percent agreement and Cohen's kappa (κ) were estimated for the presence of any ICH (yes/no), and for agreement on the Heidelberg Bleeding Classification class 1 and 2. For the Heidelberg Bleeding Classification class 1 and 2, weighted κ was estimated to take the degree of disagreement into account. RESULTS: In 297 of 300 scans, the quality of scans was sufficient to score ICH. Observers agreed on the presence or absence of any ICH in 264 of 297 scans (88.9%; κ 0.78 [95% CI, 0.71-0.85]). There was agreement on the Heidelberg Bleeding Classification class 1 and 2 and no ICH in class 1 and 2 in 226 of 297 scans (76.1%; κ 0.63 [95% CI, 0.56-0.69]; weighted κ 0.90 [95% CI, 0.87-0.93]). CONCLUSIONS: The presence of any ICH can be reliably scored on magnetic resonance imaging and can, therefore, be used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. Agreement of ICH types according to the Heidelberg Bleeding Classification is substantial and disagreements are small.

Cardiovascular Implantable Electronic Devices Enabled Remote Heart Failure Monitoring; What We Have Learned and Where to Go Next.

Despite recent developments, heart failure (HF) remains to be a great burden to the individual patient, entailing major morbidity and mortality. Moreover, HF is a great burden to overall healthcare, mainly because of frequent hospitalizations. Timely diagnosis of HF deterioration and implementation of appropriate therapy may prevent hospitalization and eventually improve a patient's prognosis; however, depending on the patient's presentation, the signs and symptoms of HF often offer too little therapeutic window to prevent hospitalizations. Cardiovascular implantable electronic devices (CIEDs) can provide real-time physiologic parameters and remote monitoring of these parameters can potentially help to identify patients at high risk. However, routine implementation of remote monitoring of CIEDs has still not been widely used in daily patient care. This review gives a detailed description of available metrics for remote HF monitoring, the studies that provide evidence of their efficacy, ways to implement them in clinical HF practice, as well as lessons learned on where to go on from where we currently are.

Comparison of the relation of the ESC 2021 and ESC 2013 definitions of left bundle branch block with clinical and echocardiographic outcome in cardiac resynchronization therapy.

INTRODUCTION: We aimed to investigate the impact of the 2021 European Society of Cardiology (ESC) guideline changes in left bundle branch block (LBBB) definition on cardiac resynchronization therapy (CRT) patient selection and outcomes. METHODS: The MUG (Maastricht, Utrecht, Groningen) registry, consisting of consecutive patients implanted with a CRT device between 2001 and 2015 was studied. For this study, patients with baseline sinus rhythm and QRS duration ≥ 130ms were eligible. Patients were classified according to ESC 2013 and 2021 guideline LBBB definitions and QRS duration. Endpoints were heart transplantation, LVAD implantation or mortality (HTx/LVAD/mortality) and echocardiographic response (LVESV reduction ≥15%). RESULTS: The analyses included 1.202, typical CRT patients. The ESC 2021 definition resulted in considerably less LBBB diagnoses compared to the 2013 definition (31.6% vs. 80.9%, respectively). Applying the 2013 definition resulted in significant separation of the Kaplan-Meier curves of HTx/LVAD/mortality (p < .0001). A significantly higher echocardiographic response rate was found in the LBBB compared to the non-LBBB group using the 2013 definition. These differences in HTx/LVAD/mortality and echocardiographic response were not found when applying the 2021 definition. CONCLUSION: The ESC 2021 LBBB definition leads to a considerably lower percentage of patients with baseline LBBB then the ESC 2013 definition. This does not lead to better differentiation of CRT responders, nor does this lead to a stronger association with clinical outcomes after CRT. In fact, stratification according to the 2021 definition is not associated with a difference in clinical or echocardiographic outcome, implying that the guideline changes may negatively influence CRT implantation practice with a weakened recommendation in patients that will benefit from CRT.

A Proteome-Wide Effect of PHF8 Knockdown on Cortical Neurons Shows Downregulation of Parkinson's Disease-Associated Protein Alpha-Synuclein and Its Interactors.

Synaptic dysfunction may underlie the pathophysiology of Parkinson's disease (PD), a presently incurable condition characterized by motor and cognitive symptoms. Here, we used quantitative proteomics to study the role of PHD Finger Protein 8 (PHF8), a histone demethylating enzyme found to be mutated in X-linked intellectual disability and identified as a genetic marker of PD, in regulating the expression of PD-related synaptic plasticity proteins. Amongst the list of proteins found to be affected by PHF8 knockdown were Parkinson's-disease-associated SNCA (alpha synuclein) and PD-linked genes DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and the PD risk gene SH3GL2 (endophilin A1). Findings in this study show that depletion of PHF8 in cortical neurons affects the activity-induced expression of proteins involved in synaptic plasticity, synaptic structure, vesicular release and membrane trafficking, spanning the spectrum of pre-synaptic and post-synaptic transmission. Given that the depletion of even a single chromatin-modifying enzyme can affect synaptic protein expression in such a concerted manner, more in-depth studies will be needed to show whether such a mechanism can be exploited as a potential disease-modifying therapeutic drug target in PD.

Incidence of premature battery depletion in subcutaneous cardioverter-defibrillator patients: insights from a multicenter registry.

BACKGROUND: The subcutaneous ICD established its role in the prevention of sudden cardiac death in recent years. The occurrence of premature battery depletion in a large subset of potentially affected devices has been a cause of concern. The incidence of premature battery depletion has not been studied systematically beyond manufacturer-reported data. METHODS: Retrospective data and the most recent follow-up data on S-ICD devices from fourteen centers in Europe, the US, and Canada was studied. The incidence of generator removal or failure was reported to investigate the incidence of premature S-ICD battery depletion, defined as battery failure within 60 months or less. RESULTS: Data from 1054 devices was analyzed. Premature battery depletion occurred in 3.5% of potentially affected devices over an observation period of 49 months. CONCLUSIONS: The incidence of premature battery depletion of S-ICD potentially affected by a battery advisory was around 3.5% after 4 years in this study. Premature depletion occurred exclusively in devices under advisory. This is in line with the most recently published reports from the manufacturer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04767516 .

Electrocardiogram-based deep learning improves outcome prediction following cardiac resynchronization therapy.

AIMS: This study aims to identify and visualize electrocardiogram (ECG) features using an explainable deep learning-based algorithm to predict cardiac resynchronization therapy (CRT) outcome. Its performance is compared with current guideline ECG criteria and QRSAREA. METHODS AND RESULTS: A deep learning algorithm, trained on 1.1 million ECGs from 251 473 patients, was used to compress the median beat ECG, thereby summarizing most ECG features into only 21 explainable factors (FactorECG). Pre-implantation ECGs of 1306 CRT patients from three academic centres were converted into their respective FactorECG. FactorECG predicted the combined clinical endpoint of death, left ventricular assist device, or heart transplantation [c-statistic 0.69, 95% confidence interval (CI) 0.66-0.72], significantly outperforming QRSAREA and guideline ECG criteria [c-statistic 0.61 (95% CI 0.58-0.64) and 0.57 (95% CI 0.54-0.60), P < 0.001 for both]. The addition of 13 clinical variables was of limited added value for the FactorECG model when compared with QRSAREA (Δ c-statistic 0.03 vs. 0.10). FactorECG identified inferolateral T-wave inversion, smaller right precordial S- and T-wave amplitude, ventricular rate, and increased PR interval and P-wave duration to be important predictors for poor outcome. An online visualization tool was created to provide interactive visualizations (https://crt.ecgx.ai). CONCLUSION: Requiring only a standard 12-lead ECG, FactorECG held superior discriminative ability for the prediction of clinical outcome when compared with guideline criteria and QRSAREA, without requiring additional clinical variables. End-to-end automated visualization of ECG features allows for an explainable algorithm, which may facilitate rapid uptake of this personalized decision-making tool in CRT.

Interatrial Block Predicts Life-Threatening Arrhythmias in Dilated Cardiomyopathy.

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life-threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P-wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter-defibrillator or anti-tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow-up, 4.4 years [2.1; 7.4]). The LTA-free survival distribution significantly differed between IAB or AF versus no IAB (both P<0.01), but not between IAB versus AF (P=0.999). This association remained statistically significant in the multivariable model (IAB: HR, 4.8 (1.4-16.1), P=0.013; AF: HR, 6.4 (1.7-24.0), P=0.007). In the external validation cohort, the survival distribution was also significantly worse for IAB or AF versus no IAB (P=0.037; P=0.005), but not for IAB versus AF (P=0.836). Conclusions IAB is an easy to assess, widely applicable marker associated with LTA in DCM. IAB and AF seem to confer similar risk of LTA. Further research on IAB in DCM, and on the management of IAB in DCM is warranted.

Physiology of Left Ventricular Septal Pacing and Left Bundle Branch Pacing.

Following the recognition of the adverse effects of right ventricular pacing, alternative permanent pacing strategies aiming to maintain a synchronous ventricular contraction have been sought. The quest for the optimal pacing site has recently led to several promising and rapidly emerging new pacing strategies, such as left ventricular septal pacing and left bundle branch pacing. In both animal and human studies, these pacing strategies seem to maintain electrical and mechanical activation of the left ventricle to a (near)physiologic level. However, more studies on the long-term effects of both strategies are needed.

Better outcome at lower costs after implementing a CRT-care pathway: comprehensive evaluation of real-world data.

AIMS: Cardiac resynchronization therapy (CRT) requires intensive, complex, and multidisciplinary care for heart failure (HF) patients. Due to limitations in time, resources, and coordination of care, in current practice, this is often incomplete. We evaluated the effect of the introduction of a CRT-care pathway (CRT-CPW) on clinical outcome and costs. METHODS AND RESULTS: The CRT-CPW focused on structuring CRT patient selection, implantation, and follow-up management. To facilitate and guarantee quality, checklists were introduced. The CRT-CPW was implemented in the Maastricht University Medical Centre in 2014. Physician-led usual care was restructured to a nurse-led care pathway. A retrospective comparison of data from CRT patients receiving usual care (2012-2014, 222 patients) and patients receiving care according to CRT-CPW (2015-2018, 241 patients) was performed. The primary outcome was the composite of all-cause mortality and HF hospitalization. Hospital-related costs of cardiovascular care after CRT implantation were analysed to address cost-effectiveness of the CRT-CPW. Demographics were comparable in the usual care and CRT-CPW groups. Kaplan-Meier estimates of the occurrence of the primary endpoint showed a significant improvement in the CRT-CPW group (25.7% vs. 34.7%, hazard ratio 0.56; confidence interval 0.40-0.78; P < 0.005), at 36 months of follow-up. The total costs for cardiology-related hospitalizations were significantly reduced in the CRT-CPW group [€17 698 (14 192-21 195) vs. 19 933 (16 980-22 991), P < 0.001]. Bootstrap cost-effectiveness analyses showed that implementation of CRT-CPW would be an economically dominant strategy in 90.7% of bootstrap samples. CONCLUSIONS: The introduction of a novel multidisciplinary, nurse-led care pathway for CRT patients resulted in significant reduction of the combination of all-cause mortality and HF hospitalizations, at reduced cardiovascular-related hospital costs.

Neurological update: consult the neurosurgical oracle for a standard operating procedure.

Standard operating procedures (SOPs) contain general instructions and principles to standardize care, to improve effective and safe healthcare. Developing new, or updating current, SOPs is, however, challenging in fields where high-level evidence is limited. Still, SOPs alone have been shown to result in less complications. In this narrative review, we describe the process of creating a consensus-based SOP that is pragmatic for clinical practice since it can be created regardless of the current level of evidence. Through live audience engagement platforms, a group of experts will be able to both anonymously respond to a created questionnaire, and (subsequently) discuss the results within the same meeting. This modified Digital Delphi method as described here can be used as a tool toward consensus-based healthcare.

Serial Assessment of Myocardial Injury Markers in Mechanically Ventilated Patients With SARS-CoV-2 (from the Prospective MaastrICCht Cohort).

Myocardial injury in COVID-19 is associated with in-hospital mortality. However, the development of myocardial injury over time and whether myocardial injury in patients with COVID-19 at the intensive care unit is associated with outcome is unclear. This study prospectively investigates myocardial injury with serial measurements over the full course of intensive care unit admission in mechanically ventilated patients with COVID-19. As part of the prospective Maastricht Intensive Care COVID cohort, predefined myocardial injury markers, including high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and electrocardiographic characteristics were serially collected in mechanically ventilated patients with COVID-19. Linear mixed-effects regression was used to compare survivors with nonsurvivors, adjusting for gender, age, APACHE-II score, daily creatinine concentration, hypertension, diabetes mellitus, and obesity. In 90 patients, 57 (63%) were survivors and 33 (37%) nonsurvivors, and a total of 628 serial electrocardiograms, 1,565 hs-cTnT, and 1,559 NT-proBNP concentrations were assessed. Log-hs-cTnT was lower in survivors compared with nonsurvivors at day 1 (ß -0.93 [-1.37; -0.49], p <0.001) and did not change over time. Log-NT-proBNP did not differ at day 1 between both groups but decreased over time in the survivor group (ß -0.08 [-0.11; -0.04] p <0.001) compared with nonsurvivors. Many electrocardiographic abnormalities were present in the whole population, without significant differences between both groups. In conclusion, baseline hs-cTnT and change in NT-proBNP were strongly associated with mortality. Two-thirds of patients with COVID-19 showed electrocardiographic abnormalities. Our serial assessment suggests that myocardial injury is common in mechanically ventilated patients with COVID-19 and is associated with outcome.

Effect of the reaction temperature on the prothrombin time and the apparent International Normalized Ratio determined with International Standards for thromboplastins.

INTRODUCTION: The definition of the International Normalized Ratio (INR) depends on a reference measurement procedure for the prothrombin time (PT) determined with international standards for thromboplastins. The agreed water bath temperature for PT determination in the reference measurement procedure is 37°C. The aim of the study was to assess the influence of small deviations of the agreed reaction temperature on PT and INR determined with World Health Organization international standards for thromboplastins rTF/16 (recombinant human) and RBT/16 (rabbit brain). METHODS: Prothrombin time was determined, with a manual hook technique, in glass test tubes in a water bath at a controlled temperature. The PT reaction temperatures were varied between 28 and 40°C. Pooled normal plasma and pooled coumarin plasma (INR ≈ 2.8) were used as test plasmas. The data were fitted to a quadratic relationship between PT and temperature. RESULTS: Prothrombin times with rTF/16 were shortened by increasing the reaction temperature up to approximately 39-40°C. PTs with RBT/16 were shortened by increasing the reaction temperature up to approximately 34-37°C, but were prolonged at higher temperatures. The apparent INR change of the coumarin plasma at 37.0°C was 0.06/°C and 0.11/°C for rTF/16 and RBT/16, respectively. CONCLUSIONS: Reaction temperature had a significant effect on PT and the apparent INR with the International Standards. At 37.0°C, the apparent INR of coumarin plasma determined with RBT/16 was more responsive to temperature change than the apparent INR determined with rTF/16. The required accuracy of the water bath temperature should be 37.0 ± 0.1°C.

Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study. METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation. CONCLUSION: Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Selective increase of correlated activity in Arc-positive neurons after chemically induced long-term potentiation in cultured hippocampal neurons.

The activity-dependent expression of immediate-early genes (IEGs) has been utilised to label memory traces. However, their roles in engram specification are incompletely understood. Outstanding questions remain as to whether expression of IEGs can interplay with network properties such as functional connectivity and also if neurons expressing different IEGs are functionally distinct. In order to connect IEG expression at the cellular level with changes in functional-connectivity, we investigated the expression of 2 IEGs, Arc and c-Fos, in cultured hippocampal neurons. Primary neuronal cultures were treated with a chemical cocktail (4-aminopyridine, bicuculline, and forskolin) to increase neuronal activity, IEG expression, and induce chemical long-term potentiation. Neuronal firing is assayed by intracellular calcium imaging using GCaMP6m and expression of IEGs is assessed by immunofluorescence staining. We noted an emergent network property of refinement in network activity, characterized by a global downregulation of correlated activity, together with an increase in correlated activity between subsets of specific neurons. Subsequently, we show that Arc expression correlates with the effects of refinement, as the increase in correlated activity occurs specifically between Arc-positive neurons. The expression patterns of the IEGs c-Fos and Arc strongly overlap, but Arc was more selectively expressed than c-Fos. A subpopulation of neurons positive for both Arc and c-Fos shows increased correlated activity, while correlated firing between Arc+/cFos- neurons is reduced. Our results relate neuronal activity-dependent expression of the IEGs Arc and c-Fos on the individual cellular level to changes in correlated activity of the neuronal network.SIGNIFICANCEEstablishing a stable long-lasting memory requires neuronal network-level changes in connection strengths in a subset of neurons, which together constitute a memory trace or engram. Two genes, c-Fos and Arc, have been implicated to play critical roles in the formation of the engram. They have been studied extensively at the cellular/molecular level, and have been used as markers of memory traces in mice. We have correlated Arc and c-Fos cellular expression with refinement of correlated neuronal activity following pharmacological activation of networks formed by cultured hippocampal neurons. Whereas there is a global loss of correlated activity, Arc-positive neurons show selectively increased correlated activity. Arc is more selectively expressed than c-Fos, but the two genes act together in encoding information about changes in correlated firing.

Therapeutic quality control in a regional thrombosis center: The effect of changing the target intensity of anticoagulation with vitamin K antagonists.

BACKGROUND: The target ranges (TR) for anticoagulation with vitamin K antagonists (VKA) in the Netherlands were changed in 2016 from INR 2.0-3.5 ('low intensity') and INR 2.5-4.0 ('high intensity') to INR 2.0-3.0 and INR 2.5-3.5, respectively. AIM: To assess the effect of the TR change on therapeutic quality control (TQC) in a Dutch regional thrombosis center taking care of approximately 3600-5500 patients annually. METHODS: TQC of chronically treated patients was assessed as the average time in therapeutic range (TTR). Evaluations were performed for non-self-management (NSM), as well as self-management patients. INR percentiles were assessed from all INR determinations in all patients, i.e. including those of induction episodes and patients treated for a short-term. RESULTS: The number of NSM patients treated chronically decreased gradually, while their average age increased, with a marginal but significant gradual increase in bleeding complications. In the period 2011-2015, i.e. before the TR change, there was a gradual increase of the TTR in NSM patients from 77.5% to 88.9% (low intensity) and from 75.3% to 84.1% (high intensity). In the same period, the median INR of all patients in the low and high intensity ranges decreased from 2.9 to 2.7, and from 3.3 to 3.2, respectively. The TTR in self-management patients remained virtually constant. After TR changes from 2016 on, the TTR of all NSM patients in the low and high intensity groups decreased to 77% and 70%, respectively, and median INRs decreased to 2.6 and 3.0, respectively. CONCLUSIONS: Introduction of internationally harmonized target ranges in 2016 resulted in further lowering of median INR values in both target ranges. As expected, TTR was reduced slightly. These findings, together with a slight increase in average age and concomitant bleeding complications, suggest that the patients on long-term VKA treatment will require intensified monitoring and treatment.