Contrast-free left atrial appendage occlusion in patients using the LAMBRE™ device.

BACKGROUND: Advances in imaging have led to procedural optimization of left atrial appendage closure (LAAC). Contrast-free approaches, guided merely by echocardiography, have been established, however data on this topic remains scarce. In this analysis, we assessed contrast-free procedural results with the LAMBRE LAAC device. METHODS: The multicenter retrospective BoBoMa (Bonn/Bordeaux/Mainz)-Registry included a total of 118 patients that underwent LAAC with LAMBRE devices omitting contrast-dye. Baseline and echocardiographic characteristics as well as intra- and postprocedural complications and outcomes were assessed. RESULTS: Patients were at a mean age of 77.5 ± 7.5 years with high thromboembolic and bleeding risk (CHADS-VASc-score 4.6 ± 1.4, HAS-BLED-score 3.7 ± 1.0, respectively). Renal function was impaired with a mean glomerular filtration rate (GFR) of 50 ± 22 ml/min. Mean procedural time was 47.2 ± 37.5  minutes with a mean radiation dose of 4.75 ± 5.25 Gy*cm2. Device success, defined as proper deployment in a correct position, was achieved in 97.5% (115/118) of cases with repositioning of the occluder in 7.6% (9/118) and resizing in 3.4% (4/118) of cases. No relevant peri-device leakage (>3 mm) was observed with 42% of occluders being implanted in an ostial position. Periprocedural complications occurred in 6.8% (8/118) of cases, including two cases of device embolization and one case of clinically-relevant pericardial effusion requiring surgical intervention. Other complications included pericardial effusion (2.5%, 3/118) and vascular access site complications (1.7%, 2/118). CONCLUSION: Echocardiography-guided contrast-free LAAC using the LAMBRE device is safe and feasible. Further prospective studies including the direct comparison of devices as well as imaging techniques are warranted in contrast-free LAAC.

Comparison of Arctic Front Advance Pro and POLARx cryoballoons for ablation therapy of atrial fibrillation: an intraprocedural analysis.

INTRODUCTION: Cryoballoon (CB) ablation has become a popular method for pulmonary vein isolation (PVI) in atrial fibrillation (AF) treatment. This study aimed to compare the intraprocedural ablation characteristics of two cryoballoons, Arctic Front Advance Pro™ (AFA-Pro, Medtronic) and POLARx™ (Boston Scientific). METHODS AND RESULTS: In this retrospective single-center study, 230 symptomatic paroxysmal or persistent AF patients underwent CB ablation with either AFA-Pro or POLARx. Propensity-score matching resulted in two cohorts of 114 patients each. Baseline and procedural characteristics were comparable between both CBs. POLARx achieved lower minimal temperatures (e.g., left superior pulmonary vein, LSPV: AFA-Pro - 49.0 °C vs. POLARx - 59.5 °C) and lower temperatures at time-to-isolation (TTI). Additionally, POLARx reached lower temperatures faster, as evidenced by lower temperatures after 40 and 60 s, and a larger mean temperature change between 20 and 40 s. POLARx also had a greater area under the curve below 0 °C and a longer thawing phase. Both CBs achieved comparable high rates of final PV-isolation. TTI, minimal esophagus temperature, and first-pass isolation rates were similar between groups. Periprocedural complications, including phrenic nerve injuries, were comparable. Troponin levels in the left atrium were elevated with both systems. Values and change in troponin were numerically higher in the POLARx group (delta troponin: AFA-Pro 36.3 (26.4, 125.4) ng/L vs. POLARx 104.9 (49.5, 122.2) ng/L), p = 0.077). CONCLUSION: AFA-Pro and POLARx are both highly effective and safe CB systems for PVI. POLARx exhibited significant faster and lower freezing characteristics, and numerically higher troponin levels might indicate greater myocardial injury. However, these differences did not translate into improved performance, procedural efficiency, or safety.

Prevention of cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation: the ODIn-AF trial.

BACKGROUND AND OBJECTIVES: Long-term oral anticoagulation (OAC) following successful catheter ablation of atrial fibrillation (AF) remains controversial. Prospective data are missing. The ODIn-AF study aimed to evaluate the effect of OAC on the incidence of silent cerebral embolic events and clinically relevant cardioembolic events in patients at intermediate to high risk for embolic events, free from AF after pulmonary vein isolation (PVI). METHODS: This prospective, randomized, multicenter, open-label, blinded endpoint interventional trial enrolled patients who were scheduled for PVI to treat paroxysmal or persistent AF. Six months after PVI, AF-free patients were randomized to receive either continued OAC with dabigatran or no OAC. The primary endpoint was the incidence of new silent micro- and macro-embolic lesions detected on brain MRI at 12 months of follow-up compared to baseline. Safety analysis included bleedings, clinically evident cardioembolic, and serious adverse events (SAE). RESULTS: Between 2015 and 2021, 200 patients were randomized into 2 study arms (on OAC: n = 99, off OAC: n = 101). There was no significant difference in the occurrence of new cerebral microlesions between the on OAC and off OAC arm [2 (2%) versus 0 (0%); P = 0.1517] after 12 months. MRI showed no new macro-embolic lesion, no clinical apparent strokes were present in both groups. SAE were more frequent in the OAC arm [on OAC n = 34 (31.8%), off OAC n = 18 (19.4%); P = 0.0460]; bleedings did not differ. CONCLUSION: Discontinuation of OAC after successful PVI was not found to be associated with an elevated risk of cerebral embolic events compared with continued OAC after a follow-up of 12 months.

The CT derived angle between the transseptal puncture site and the left atrial appendage as a predictor for complex interventional occlusion procedures.

OBJECTIVE: To evaluate the role of the CT-derived angle between the intra-atrial septum (IAS) and the left atrial appendage (LAA) on procedural complexity and clinical outcomes in left atrial appendage occlusion (LAAO) procedures. BACKGROUND: Given the broad variations in anatomy, LAAO remains one of the most challenging interventional procedures in structural heart disease. In recent years, preprocedural cardiac tomography (CT) has evolved as a valuable tool; however, prediction of procedural complexity remains cumbersome. METHODS: We retrospectively analyzed 47 patients that underwent LAAO at our center in whom pre-procedural cardiac CT-scans were available. Among other baseline parameters, we measured the angle between the LAA ostium and the preferred transseptal puncture site at the IAS. We compared patients with an angle above and below the median regarding procedural characteristics and procedural outcome. RESULTS: The median angle between the LAA and the IAS was 127.3° (IQR: 120.9-141.3). LAAO took longer in patients with a measured angle below the median (55.0 ± 22.7 min vs. 41.3 ± 17.5 min; p = .04), resulting in longer radiation times (13.0 ± 5.3 min vs. 9.8 ± 5.7 min; p = .04) and more contrast use (61.1 ± 47.5 mL vs. 33.6 ± 24.7 mL; p = .05). Moreover, the necessity for a sheath exchange was significantly higher (30.4% vs. 4.2%, p = .02) and device repositioning or device resizing trended to be more frequent (26.1% vs. 8.3%; p = .1 and 21.7% vs. 8.3%; p = .2). There were no differences in procedural outcome, device-position and peri-device leak (PDL). CONCLUSIONS: The angle between the transseptal puncture site and the LAA ostium may serve as a predictor for more demanding LAAO interventions. In our study a steeper angle led to a prolonged procedure resulting in higher doses of contrast and radiation, but was not associated with a worse procedural outcome.

Cardiac autonomic dysfunction in adult congenital heart disease.

PURPOSE: Due to recent advances in diagnosis and treatment, the number of adults with congenital heart disease (ACHD) has substantially increased. This achievement is mitigated by rhythm disorders. Here, we sought to determine alterations in heart rate variability (HRV) and their prognostic value in ACHD. METHODS: Ninety seven ACHD patients (39.2 ± 14.1 years, 51.5% female) and 19 controls (39.7 ± 15.0 years, 47.4% female) underwent 24-h Holter monitoring. RESULTS: As compared to controls, ACHD patients offered a significantly higher burden of premature ventricular contractions (p = 0.02) and decreased HRV indices (natural logarithmic transformation of very low frequency (lnVLF): 7.46 ± 0.76 ms2 vs. 7.91 ± 0.92ms2, p = 0.03; natural logarithmic transformation of low frequency (lnLF): 6.39 ± 0.95ms2 vs. 7.01 ± 1.07ms2, p = 0.01; natural logarithmic transformation of the ratio of low to high frequency spectra (lnLF/HF): 0.81 ± 0.74 vs. 1.17 ± 0.51, p = 0.04). No differences in HRV measures were observed across ACHD lesion groups. NT-proBNP levels were significantly related to both time and frequency domain indices (natural logarithmic transformation of the standard deviation of NN intervals (lnSDNN): Spearman´s rho = -0.32, p = 0.001; natural logarithmic transformation of the standard deviation of the average NN intervals for each 5-min segment of a 24-h Holter monitoring (lnSDANN): Spearman´s rho: -0.33, p = 0.001; natural logarithmic transformation of the total power (lnTP): Spearman´s rho: -0.25, p = 0.01; lnVLF: Spearman´s rho: -0.33, p = 0.001; lnLF: Spearman´s rho: -0.35, p < 0.001; lnLF/HF: Spearman´s rho: -0.34, p = 0.001). After a mean follow-up of 3.9 ± 0.7 years, 8 patients died and 3 patients survived sudden cardiac death (SCD). Several HRV parameters were significantly higher in event-free ACHD patients than in those who died or survived SCD (natural logarithmic transformation of the average of the standard deviations of NN intervals for each 5-min segment of a 24-h Holter monitoring (lnASDNN): p = 0.04; lnPNN30: p = 0.04; lnVFL: p = 0.03; lnLF: p < 0.01). On univariate Cox regression analysis, the time domain indices lnSDNN, lnASDNN and lnPNN30, as well as the frequency domain parameters lnTP, lnVLF and lnLF were associated with death and survived cardiac arrest. CONCLUSION: ACHD is accompanied by HRV impairment that carries prognostic implications on ACHD mortality and survived SCD.

Symptomatic vs. non-symptomatic device-related thrombus after LAAC: a sub-analysis from the multicenter EUROC-DRT registry.

BACKGROUND: Device-related thrombus (DRT) after left atrial appendage closure (LAAC) is associated with adverse outcomes, i.e. ischemic stroke or systemic embolism (SE). Data on predictors of stroke/SE in the context of DRT are limited. AIMS: This study aimed to identify predisposing factors for stroke/SE in DRT patients. In addition, the temporal connection of stroke/SE to DRT diagnosis was analyzed. METHODS: The EUROC-DRT registry included 176 patients, in whom DRT after LAAC were diagnosed. Patients with symptomatic DRT, defined as stroke/SE in the context of DRT diagnosis, were compared against patients with non-symptomatic DRT. Baseline characteristics, anti-thrombotic regimens, device position, and timing of stroke/SE were compared. RESULTS: Stroke/SE occurred in 25/176 (14.2%) patients diagnosed with DRT (symptomatic DRT). Stroke/SE occurred after a median of 198 days (IQR 37-558) after LAAC. In 45.8% stroke/SE occurred within one month before/after DRT diagnosis (DRT-related stroke). Patients with symptomatic DRT had lower left ventricular ejection fractions (50.0 ± 9.1% vs. 54.2 ± 11.0%, p = 0.03) and higher rates of non-paroxysmal atrial fibrillation (84.0% vs. 64.9%, p = 0.06). Other baseline parameters and device positions were not different. Most ischemic events occurred among patients with single antiplatelet therapy (50%), however, stroke/SE was also observed under dual antiplatelet therapy (25%) or oral anticoagulation (20%). CONCLUSION: Stroke/SE are documented in 14.2% and occur both in close temporal relation to the DRT finding and chronologically independently therefrom. Identification of risk factors remains cumbersome, putting all DRT patients at substantial risk for stroke/SE. Further studies are necessary to minimize the risk of DRT and ischemic events.

Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na+/Ca2+ exchanger knockout mice.

Aims: Na+/Ca2+ exchanger (NCX) upregulation in cardiac diseases like heart failure promotes as an independent proarrhythmic factor early and delayed afterdepolarizations (EADs/DADs) on the single cell level. Consequently, NCX inhibition protects against EADs and DADs in isolated cardiomyocytes. We here investigate, whether these promising cellular in vitro findings likewise apply to an in vivo setup. Methods/Results: Programmed ventricular stimulation (PVS) and isoproterenol were applied to a murine heterozygous NCX-knockout model (KO) to investigate ventricular arrhythmia initiation and perpetuation compared to wild-type (WT). KO displayed a reduced susceptibility towards isoproterenol-induced premature ventricular complexes. During PVS, initiation of single or double ectopic beats was similar between KO and WT. But strikingly, perpetuation of ventricular tachycardia (VT) was significantly increased in KO (animals with VT - KO: 82 %; WT: 47 %; p = 0.0122 / median number of VTs - KO: 4.5 (1.0, 6.25); WT: 0.0 (0.0, 4.0); p = 0.0039). The median VT duration was prolonged in KO (in s; KO: 0.38 (0.19, 0.96); WT: 0.0 (0.0, 0.60); p = 0.0239). The ventricular refractory period (VRP) was shortened in KO (in ms; KO: 15.1 ± 0.7; WT: 18.7 ± 0.7; p = 0.0013). Conclusions: Not the initiation, but the perpetuation of provoked whole-heart in vivo ventricular arrhythmia was increased in KO. As a potential mechanism, we found a significantly reduced VRP, which may promote perpetuation of reentrant ventricular arrhythmia. On a translational perspective, the antiarrhythmic concept of therapeutic NCX inhibition seems to be ambivalent by protecting from initiating afterdepolarizations but favoring arrhythmia perpetuation in vivo at least in a murine model.

Clinical and echocardiographic risk factors for device-related thrombus after left atrial appendage closure: an analysis from the multicenter EUROC-DRT registry.

BACKGROUND: Data on Device-related Thrombus (DRT) after left atrial appendage closure (LAAC) remain scarce. This study aimed to investigate risk factors for DRT from centers reporting to the EUROC-DRT registry. METHODS: We included 537 patients (112 with DRT and 425 without DRT) who had undergone LAAC between 12/2008 and 04/2019. Baseline and implantation characteristics, anti-thrombotic treatment and clinical outcomes were compared between both groups in uni- and multivariate analyses. Additional propensity-score matching (PSM) was conducted to focus on the role of implantation characteristics. RESULTS: Patients with DRT showed higher rates of previous stroke/transient ischemic attack (TIA) (49.1% vs. 34.7%, p < 0.01), spontaneous echocardiographic contrast (SEC) (44.9% vs. 27.7%, p < 0.01) and lower left atrial appendage (LAA) peak emptying velocity (35.4 ± 18.5 vs. 42.4 ± 18.0 cm/s, p = 0.02). Occluders implanted in DRT patients were larger (25.5 ± 3.8 vs. 24.6 ± 3.5 mm, p = 0.03) and implanted deeper in the LAA (mean depth: 7.6 ± 4.7 vs. 5.7 ± 4.7 mm, p < 0.01). Coverage of the appendage ostium was achieved less often in DRT patients (69.5% vs. 81.5%, p < 0.01), while DRT patients were less frequently on oral anticoagulation (7.1% vs. 16.7%, p < 0.01). Multivariate analysis identified age, prior stroke/TIA and SEC as independent risk factors for DRT. After PSM, implantation depth was found to be predictive. Rates of stroke/TIA were higher in DRT patients (13.5% vs. 3.8%, Hazard Ratio: 4.21 [95%-confidence interval: 1.88-9.49], p < 0.01). CONCLUSIONS: DRT after LAAC is associated with adverse outcome and appears to be of multifactorial origin, depending on patient characteristics, anticoagulation regimen and device position.

Assessment of LAA Strain and Thrombus Mobility and Its Impact on Thrombus Resolution-Added-Value of a Novel Echocardiographic Thrombus Tracking Method.

PURPOSE: The mobility of left atrial appendage (LAA) thrombi and changes hereof under anticoagulation may serve as a marker of both risk of embolism and efficacy of treatment. In this study, we sought to evaluate thrombus mobility and hypothesized that LAA dynamics and thrombus mobility could serve as a baseline marker of thrombus dissolvability. METHODS: Patients with two-dimensional transesophageal echocardiographic images of the LAA, and with evidence of LAA thrombus were included in this study. Using a speckle tracking algorithm, functional information from the LAA and thrombi of different patients was computed. While the LAA motion was quantified through the longitudinal strain, thrombus mobility was evaluated using a novel method by directly tracking the thrombus, isolated from the global cardiac motion. Baseline characteristics and echocardiographic parameters were compared between responders (thrombus resolution) and non-responders (thrombus persistence) to anticoagulation. RESULTS: We included 35 patients with atrial fibrillation with evidence of LAA thrombi. Patients had a mean age of 72.9 ± 14.1 years, exhibited a high risk for thromboembolism (CHA2DS2-VASc-Score 4.1 ± 1.5) and had moderately reduced LVEF (41.7 ± 14.4%) and signs of diastolic dysfunction (E/E' = 19.7 ± 8.5). While anticoagulation was initiated in all patients, resolution was achieved in 51.4% of patients. Significantly higher LAA peak strain (- 3.0 ± 1.3 vs. - 1.6 ± 1.5%, p < 0.01) and thrombus mobility (0.33 ± 0.13 mm vs. 0.18 ± 0.08 mm, p < 0.01) were observed in patients in whom thrombi resolved (i.e. responders against non-responders). Receiver operating characteristic (ROC) analysis revealed a high discriminatory ability for thrombus mobility with regards to thrombus resolution (AUC 0.89). CONCLUSION: Isolated tracking of thrombus mobility from echocardiographic images is feasible. In patients with LAA thrombus, higher thrombus mobility appeared to be associated with thrombus resolution. Future studies should be conducted to evaluate the role of the described technique to predict LAA thrombus resolution or persistence.

Large extracellular vesicles in the left atrial appendage in patients with atrial fibrillation-the missing link?

Atrial fibrillation (AF) is the most frequent arrhythmic disease in humans, which leads to thrombus formation in the left atrial appendage and stroke through peripheral embolization. Depending on their origin, large extracellular vesicles (lEVs) can exert pro-coagulant functions. In the present study, we investigated how different types of AF influence the levels of large EV subtypes in three distinct atrial localizations. Blood samples were collected from the right and left atrium and the left atrial appendage of 58 patients. 49% of the patients had permanent AF, 34% had non-permanent AF, and 17% had no history of AF. Flow cytometric analysis of the origin of the lEVs showed that the proportion of platelet-derived lEVs in the left atrial appendage was significantly higher in permanent AF patients compared to non-permanent AF. When we grouped patients according to their current heart rhythm, we also detected significantly higher levels of platelet-derived lEVs in the left atrial appendage (LAA) in patients with atrial fibrillation. In vitro studies revealed, that platelet activation with lipopolysaccharide (LPS) leads to higher levels of miR-222-3p and miR-223-3p in platelet-derived lEVs. Treatment with lEVs from LPS- or thrombin-activated platelets reduces the migration of endothelial cells in vitro. These results suggest that permanent atrial fibrillation is associated with increased levels of platelet-derived lEVs in the LAA, which are potentially involved in LAA thrombus formation.

Incidence, persistence, and clinical relevance of iatrogenic atrial septal defects after percutaneous left atrial appendage occlusion.

OBJECTIVE: To investigate the rate and clinical impact of a persisting iatrogenic atrial septal defect (iASD) after percutaneous left atrial appendage occlusion (LAAO). BACKGROUND: Percutaneous LAAO is an alternative to oral anticoagulation (OAC) for the prevention of ischemic stroke and systemic embolism in patients with atrial fibrillation (AF). Data regarding incidence and persistence of iASD after LAAO procedures and its clinical relevance is scarce. METHODS: We retrospectively analyzed 144 patients that underwent LAAO at our center between 2009 and 2020 who had at least one follow-up including transesophageal echocardiography (TEE). Baseline clinical, procedural data and echocardiographic characteristics in patients with and without evidence of an iASD were compared. We furthermore determined the rate of iASD persistence over time and evaluated outcomes of patients with and without spontaneous iASD closure. RESULTS: After a median of 92 days (IQR 75-108 days) after LAAO, 50 patients (50/144, 34.7%) showed evidence of an iASD. Patients with iASD had higher CHADS-VASc-scores (4.9±1.5 vs 4.2±1.2, p = 0.03), larger left atrial volumes (80.5±30.5 ml vs 67.1±19.7 ml, p = 0.01) and were more likely to have relevant mitral regurgitation (≥° II) (46.0% vs 12.3%, p = 0.001). LAAO procedures took longer (50.1±24.3 vs 41.1±17.8 min, p = 0.06) in patients with a persisting iASD. Furthermore, larger device sizes were implanted (24.3±3.4 mm vs 22.1±2.8 mm, p = 0.03). The presence of an iASD had no impact on RV dysfunction, thromboembolism or mortality. Spontaneous closure of an iASD was documented in 52.0% (26/50). Hereby, similar risk factors were identified for the persistence of an iASD in follow-up.

CHA2DS2-VASC score predicts coronary artery disease progression and mortality after ventricular arrhythmia in patients with implantable cardioverter-defibrillator.

AIM: The CHA2DS2-VASC score has expanded its use beyond the initial purpose of predicting the risk of stroke in patients with atrial fibrillation. We aimed to investigate the value of the CHA2DS2-VASC score as a risk assessment tool to predict relevant coronary artery disease (CAD) leading to percutaneous coronary intervention (PCI), and all-cause mortality after detected ventricular arrhythmia (VA) in patients with an Implantable Cardioverter-Defibrillator (ICD). METHODS: A total of 183 ICD-patients who underwent coronary angiography after VA were included and classified according to their CHA2DS2-VASC score in a low(1-3), intermediate(4-5) and high(6-8) score group. We evaluated the predictive value of CHA2DS2-VASC score for the presence of relevant CAD leading to percutaneous coronary intervention (PCI), as well as late all-cause mortality. RESULTS: A total of 60 patients (32.8%) had significant CAD and underwent successful PCI. After adjustment for relevant parameters such as ischemic cardiomyopathy, angina pectoris, left ventricular ejection fraction, CHA2DS2-VASC score remained the only independent predictor of CAD leading to PCI [HR 1.73 (1.07-2.80)]. The Area under curve was 0.64 (0.56-72, p = 0.002). Kaplan-Meier analysis and log-rank showed an increased three-year mortality of ICD-patients with an intermediate or high score after VA (p = 0.003). Multivariate cox-regression analysis revealed that CHA2DS2-VASC score was also independently associated with all-cause mortality following adjustment for clinically relevant variables (HR 2.20, 1.17-4.14). CONCLUSIONS: CHA2DS2-VASC score can be a predictor of CAD leading to PCI in ICD-patients after VA. ICD-Patients with a high score have an increased risk for reduced three-year all-cause mortality after VA.

Device-Related Thrombus After Left Atrial Appendage Closure: Data on Thrombus Characteristics, Treatment Strategies, and Clinical Outcomes From the EUROC-DRT-Registry.

BACKGROUND: Left atrial appendage closure is an established therapy in patients with atrial fibrillation. Although device-related thrombosis (DRT) is relatively rare, it is potentially linked to adverse events. As data on DRT characteristics, outcome, and treatment regimen are scarce, we aimed to assess these questions in a multicenter approach. METHODS: One hundred fifty-six patients with the diagnosis of DRT after left atrial appendage closure were included in the multinational EUROC-DRT registry. Baseline characteristics included clinical and echocardiographic data. After inclusion, all patients underwent further clinical and echocardiographic follow-up to assess DRT dynamics, treatment success, and outcome. RESULTS: DRT was detected after a median of 93 days (interquartile range, 54­161 days) with 17.9% being detected >6 months after left atrial appendage closure. Patients with DRT were at high ischemic and bleeding risk (CHA2DS2-VASc 4.5±1.7, HAS-BLED 3.3±1.2) and had nonparoxysmal atrial fibrillation (67.3%), previous stroke (53.8%), and spontaneous echo contrast (50.6%). The initial treatment regimens showed comparable resolution rates (antiplatelet monotherapy: 57.1%, dual antiplatelet therapy: 85.7%, vitamin K antagonists: 80.0%, novel oral anticoagulants: 75.0%, and heparin: 68.6%). After intensification or switch of treatment, complete DRT resolution was achieved in 79.5% of patients. Two-year follow-up revealed a high risk of mortality (20.0%) and ischemic stroke (13.8%) in patients with DRT. Patients with incomplete DRT resolution showed numerically higher stroke rates and increased mortality rates (stroke: 17.6% versus 12.3%, P=0.29; mortality: 31.3% versus 13.1%, P=0.05). CONCLUSIONS: A substantial proportion of DRT is detected >6 months after left atrial appendage closure, highlighting the need for imaging follow-up. Patients with DRT appear to be at a high risk for stroke and mortality. While DRT resolution was achieved in most patients, incomplete DRT resolution appeared to identify patients at even higher risk. Optimal DRT diagnostic criteria and treatment regimens are warranted.

Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress.

Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1-/-) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1-/- mice to chronic social defeat stress (CSDS). Cnr1-/- mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1-/- mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1-/- mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1-/- mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.

Incidence, predictors and outcomes of device-related thrombus after left atrial appendage closure with the WATCHMAN device-Insights from the EWOLUTION real world registry.

BACKGROUND: In this analysis of the EWOLUTION registry, we evaluated the incidence, relevance and predictors of device-related thrombus in a large multi-center real-world cohort undergoing LAAc with the WATCHMAN device. METHODS AND RESULTS: We analyzed the 835 patients who underwent percutaneous LAA closure with the WATCHMAN device in the EWOLUTION registry in whom at least one TEE follow up was performed. Patients were 74 ± 9 y/o and were at high risk for stroke and bleeding (CHA2DS2-VASC-Score 4.3 ± 1.7; HAS-BLED-Score 2.3 ± 1.2). Device-related thrombus was detected in 4.1% (34/835) after a median of 54 days (IQR 42-111 days) with 91.2% (31/34) being detected within 3 months after the procedure or at the time of first TEE. Hereby DRT occurred irrespective of postprocedural anticoagulation. Patients with DRT more frequently had long-standing, non-paroxysmal atrial fibrillation (82.4 vs. 64.9%, p < .01), evidence of dense spontaneous echo contrast (26.5 vs. 11.9%, p = .03) and larger LAA diameters at the ostium (22.8 ± 3.5 vs. 21.1 ± 3.5 mm, p < .01) compared to patients without DRT. Left ventricular ejection fraction, device compression ratio and the incidence of renal dysfunction did not differ between the two groups. In a multivariate analysis, only non-paroxysmal atrial fibrillation identified as an independent predictor of developing DRT. Specific treatment of DRT was initiated in 62% (21/34) of patients whereas resolution was confirmed in 86% (18/21) of cases. Overall, no significant differences in annual rates of stroke/TIA or systemic embolism were observed in patients with or without DRT (DRT 1.7 vs. No-DRT 2.2%/year, p = .8). CONCLUSIONS: In real-world patients undergoing LAAc with the WATCHMAN device, DRT is rare. DRT was most frequently detected within the first 3 months after LAAc regardless of post-procedural regimen and was not associated with an increased risk of stroke or SE. While long-standing atrial fibrillation was the only independent factor associated with DRT, medical treatment of DRT resulted in a resolution of thrombi in most cases.

Single tests of implantable cardioverter defibrillators can be performed in selected patients at a low risk of neuronal damage.

BACKGROUND: Defibrillator testing (DFT) is still used in selected patients to ensure adequate therapy. To do so, ventricular fibrillation is induced and terminated by the implanted cardioverter defibrillator (ICD). Studies have shown increases in neuronal damage markers without a measurable clinical effect in patients after defibrillator threshold testing with multiple shocks. OBJECTIVE: The aim of this study was to measure clinical outcomes, neuronal damage parameters (NSE and S100), and intraoperative cerebral perfusion (Doppler, near infra-red spectroscopy [NIRS]) in patients undergoing single DFT after transvenous ICD implantation and comparing them to untested patients. METHOD: We included 23 patients. Nine underwent surgery with a single DFT, 14 were not tested. Cognitive impairment was tested using the Mini-Mental-Status Test (MMST) and the DEMTECt 24 h prior and postsurgery. We also measured S100 and Neuron-Specific Enolase (NSE) at these timepoints. During surgery we measured medial cerebral artery velocity and cerebral tissue oxygen saturation (rSO2 ). RESULTS: We found no significant differences between the patient groups except for a significant increase in mean arterial blood pressure and an increase in rSO2 after testing. One patient with cerebral vasculopathy had a significant increase in his NSE values without showing clinical symptoms. This patient also had low rSO2 measurements and a decrease in medial cerebral artery velocity after DFT, other than the other patients. CONCLUSION: Single DFT did not lead to signs of neuronal damage or cognitive impairment except in one case with pre-existing cerebral vasculopathy. Therefore, our results support the use of DFT in carefully selected patients.

Clinical outcomes and thrombus resolution in patients with solid left atrial appendage thrombi: results of a single-center real-world registry.

BACKGROUND: Data on thrombus resolution and clinical outcome data after a therapy of LAA thrombus with novel oral anticoagulants (NOACs) are scarce. METHODS: In this single-center study, we retrospectively analyzed 78 patients diagnosed with a solid LAA thrombus by transesophageal echocardiography (TEE). We assessed baseline clinical and echocardiographic characteristics, the anticoagulatory regimens and outcomes of patients with (responders) and without (non-responders) thrombus resolution. RESULTS: Mean age was 76.1 ± 8.3 years, patients were male in 57.7% and presented with a high risk for thromboembolism (CHA2DS2-VASc: 4.3 ± 1.1). At thrombus diagnosis, 44.9% patients were treated with a NOAC, while 41.0% were under therapy with a VKA. Complete thrombus resolution was achieved after a mean of 116 ± 79 days in a total of 51.3% of patients, 35.9% showed a reduction of thrombus size, whereas 12.8% showed no changes in thrombus dimensions. There was no statistically significant difference in the rate of LAA thrombus resolution between VKA and NOACs (41.2 vs. 57.1%, p = 0.18). However, in cases in which only the therapy with a NOAC led to complete thrombus resolution, the time needed was significantly shorter than with VKA (81 ± 38 vs. 129 ± 46 days, p = 0.03). Regarding safety outcomes, no differences in bleeding or thromboembolism were observed between patients with and without thrombus resolution. CONCLUSIONS: In this registry, approximately 85% of LAA thrombi were diagnosed in patients with ongoing OAC. Thrombus resolution was observed in nearly 50% of cases. Although there was no difference in the rate of LAA thrombus resolution between VKA and NOACs, the resolution time was shorter in patients prescribed a NOAC.

Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice.

BACKGROUND: Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p.R350P. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WT-TAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 µl/min, HET sham: 10391 ± 1349µl/min, WT-TAC: 8097 ± 1903µl/min, HET-TAC: 5793 ± 2517µl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. CONCLUSION: Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.