Pulsed-field- vs. cryoballoon-based pulmonary vein isolation: lessons from repeat procedures

Aims: Pulsed-field ablation (PFA) is an emerging technology to perform pulmonary vein isolation (PVI). Initial data demonstrated high safety and efficacy. Data on long-term PVI durability and reconduction patterns in comparison to established energy sources for PVI are scarce. We compare findings in repeat ablation procedures after a first PFA to findings in repeat ablation procedures after a first cryoballoon ablation (CBA) based PVI. Methods and result: A total of 550 consecutively enrolled patients underwent PFA or CBA index PVI. Repeat ablations in patients with symptomatic atrial arrhythmia recurrences were analysed. A total of 22/191 (12%) patients after index PFA-PVI and 44/359 (12%) after CBA-PVI underwent repeat ablation. Reconduction of any pulmonary vein (PV) was detected by multipolar spiral mapping catheter at each PV with careful evaluation of PV potentials and by 3D-mapping in 16/22 patients (73%) after PFA-PVI and in 33/44 (75%) after CBA-PVI (P = 1.000). Of 82 initially isolated PVs after PFA-PVI, 31 (38%) were reconducting; of 169 isolated PVs after CBA-PVI, 63 (37%) were reconducting (P = 0.936). Clinical atrial tachycardia occurred similarly in patients after PFA (5/22; 23%) and CBA (7/44; 16%; P = 0.515). Roof lines were set more often after PFA- (8/22; 36%) compared with CBA-PVI (5/44; 11%; P = 0.023). Repeat procedure duration [PFA: 87 (76, 123) min; CBA: 93 (75, 128) min; P = 0.446] was similar and fluoroscopy time [PFA: 11 (9, 14) min; CBA: 11 (8, 14) min; P = 0.739] equal between groups at repeat ablation. Conclusion: During repeat ablation after previous PFA- or CBA-based PVI, electrical PV-reconduction rates and patterns were similar

Functional evaluation of the PTPase DEP-1 as a novel regulator of monocytes and macrophages in diabetes and inflammation

Monozyten und Makrophagen spielen im Kontext von Diabetes mellitus und Atherosklerose eine wichtige Rolle. In der vorliegenden Arbeit wurde die Protein-Tyrosin-Phosphatase Density-enhanced phosphatase I (DEP-1) im Kontext von Diabetes in einem Hyperglykaemie- und Inflammationsmodell in Monozyten und Makrophagen charakterisiert. Es konnte gezeigt werden, dass die Expression von DEP-1 in Monozyten von Diabetikern im Vergleich zu Nicht-Diabetikern erhöht ist. In-vitro war DEP-1 in Monozyten unter Stimulation mit TNF-alpha, sowie unter hyperglykaemischen Bedingungen ebenfalls heraufreguliert. M1-Makrophagen zeigten die hoechste Proteinexpression, sowie eine erhoehte DEP-1 Phosphatase-Aktivitaet im Vergleich nicht-aktivierten und M2-aktivierten Makrophagen. siRNA basiertes Silencing von DEP-1 fuehrte zu reduzierter Migration von Makrophagen im Wundheilungsversuch. Die p65-Expression, die p65-Phosphorylierung und die TNF-alpha Expression waren in Makrophagen unter Silencing der Phosphatase erhoeht.Monocytes and macrophages play crucial roles in the pathophysiological context of diabetes mellitus and atherosclerosis. The present work characterizes the protein tyrosine phosphatase Density-enhanced phosphatase 1 (DEP-1) in the context of diabetes by employing a model of hyperglycemia and inflammation in monocytes and macrophages. DEP-1 mRNA expression was upregulated in monocytes from diabetic versus non-diabetic patients. In monocytes, stimulation with TNF-alpha as well as culturing in hyperglycemia led to increased protein expression of DEP-1. M1-activated macrophages showed highest protein expression and a significantly increased phosphatase activity of DEP-1 in comparison with non-activated and alternatively activated M2-macrophages. siRNA-based silencing of DEP-1 led to reduced macrophage migration in a wound-heeling assay. Expression of p65 and p65-phosphorylation, as well as expression of TNF-alpha in macrophages was increased after silencing of the phosphatase

An enigmatic case of cortical anopsia: Antemortem diagnosis of a 14-3-3 negative Heidenhain-variant MM1-sCJD

Sporadic Creutzfeldt-Jakob disease is the predominant type of human prion disease. While routine diagnostic in phenotypic cases has advanced considerably, the clinical heterogeneity and rarity of subtypes continue to constitute a major clinical and diagnostic challenge. Here, we report a peculiar case of the Heidenhain-variant of MM1 sporadic Creutzfeldt-Jakob disease presenting as a stroke mimic in an 81-year-old patient with a rapid and clinically distinct course of disease as compared to previously reported cases. While 14-3-3 protein was negative, clinical findings substantiated by 18F-FDG-PET imaging and RT-QuIC-Assay were able to establish the diagnosis. We conclude that in cases presenting with rapid progressive dementia secondary to sudden cortical anopsia the Heidenhain-variant of CJD should be considered

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

Purpose: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. Methods: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. Results: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. Conclusions: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects

Repeat pulmonary vein isolation and anterior line ablation using a novel point-by-point pulsed-field ablation system

Background Pulsed-field ablation (PFA) is a nonthermal energy source for ablation of cardiac arrhythmias. This study investigated the prospective outcomes of a novel PFA generator in conjunction with a commercially available, contact force-sensing, focal ablation catheter. Objective The purpose of this study was to assess the feasibility, safety, and lesion characteristics of point-by-point PFA in consecutive patients undergoing repeat ablation of atrial fibrillation (AF). Methods The study involved reisolation of pulmonary veins (PVs) with electrical reconnection and the creation of an anterior line (AL) in patients with anterior substrate or durable pulmonary vein isolation (PVI). Results In 24 patients (46% female; mean age 67 ± 10 years; 67% persistent AF), successful reisolation of 27 of 27 reconnected PVs (100%) was performed. In 19 patients, AL ablation was performed, with bidirectional block in 16 (84%), median ablation time 26 [21, 33] minutes, and first-pass bidirectional block in 13 patients (68%). Acute AL reconduction occurred in 8 of 19 patients (42%). Among these 8 patients, a subsequent sustained block of the AL was achieved in 5 (63%). Ultra-high-density electroanatomic mapping revealed homogeneous but relatively large low-voltage areas in the ablated regions. Median procedural, left atrial dwell, and fluoroscopy times were 100 [90, 109] minutes, 83 [75, 98] minutes, and 10 [8, 13] minutes, respectively. No major or minor complications occurred. Conclusion This study demonstrated feasibility, acute efficacy, and safety of point-by-point PFA for repeat PVI and AL ablation. Further studies are warranted to assess the long-term durability and comparison with established ablation methods