bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin K2 and the Vitamin-K-Cycle-Enzyme VKORC1L1 improve endothelial regeneration by inhibiting endothelial-mesenchymal transition, inflammatory cell activation and ferroptosis
Authors: Al Zaidi M , Repges E , Tiyerili V , Oldenburg J , Jansen F , Nickenig G , Zimmer S , Aksoy A 
Published: October 2024

Abstract

Introduction
Vascular inflammation is a crucial contributor to atherosclerosis, in which oxidative stress, endoplasmic reticulum (ER) stress and transition of endothelial to mesenchymal cells (EndMT) are of critical importance.
Vitamin-K-antagonists (VKA) promote vascular dysfunction, while dietary vitamin K intake was proposed to reduce incidence of coronary artery disease, but the mechanisms remain unresolved. Key enzyme for regeneration of vitamin K is the Vitamin K epoxide reductase complex subunit 1 (VKORC1), which also represents the pharmacological target of VKA. VKOR-like1 (VKORC1L1) is an isoenzyme of VKORC1, which resides at the ER-membrane, exerts antioxidative properties and is involved in vitamin K maintenance.
Aim of this study was to investigate the role of Vitamin K2 and the VKOR-enzymes in endothelial cell inflammation.

Methods and Results
In human coronary artery endothelial cells (HCAEC), Vitamin K2 improves endothelial regeneration by increasing proliferation and cell viability and by reducing both apoptosis and ferroptosis (relative viability: RSL3 0.11 ± 0.01 vs 0.32 ± 0.05 RSL3+K2-1µM vs. 0.44 ± 0.11 RSL3+K2-10µM, p&lt;0.001). Moreover, Vitamin K2-supplementation inhibits EndMT by reducing expression of mesenchymal markers (Calponin, SM22; Fig.1).
In silico analyses of the proteome of human coronary atherosclerosis revealed increased expression of VKORC1L1, but not of VKORC1. In vitro induction of oxidative stress and ER-Stress promoted time- and dose-dependent enhanced expression of VKORC1L1, without altering VKORC1 expression (H2O2: 2.3-fold vs. 0.8-fold after 40 minutes, p=0.04; tunicamycin: 1 μg/ml: 1.43-fold vs. 0.8-fold, p&lt;0.01). Likewise, siRNA-mediated VKORC1L1 knockdown induces an inflammatory gene signature with upregulation of NFkB-signalling and endoplasmic reticulum stress (NF-κB: 1.95-fold ± 0.13, GRP78: 1.32-fold ± 0.04 vs. control, p&lt;0.01). Furthermore, VKORC1L1 downregulation increased formation of reactive oxygen species (ROS) and reduced proliferation (EdU signal: 0.56 ± 0.02 vs. control, p &lt; 0.01). In contrast, VKORC1-knockdown does not impair endothelial regeneration and function (Fig.2). Vitamin K2 reduces vascular inflammation and endoplasmic reticulum stress in the case of VKORC1-, but not VKORC1L1-knockdown. In addition, inducing EndMT resulted in a reduction of VKORC1L1, but not of VKORC1, while VKORC1L1-knockdown aggravates EndMT.

Conclusion
VKORC1 and its isoenzyme VKORC1L1 exhibit divergent effects on endothelial cell inflammation. Further studies are warranted to shed light on the regulation of the enzymes to improve our understanding regarding vascular side effects of VKA treatment and beneficial effects of vitamin K supplementation.
Association of telomeres length with cardiovascular risk factors and arterial stiffness
Authors: Sagris M , Theofilis P T , Oikonomou E O , Toupance S T , Benetos A B , Vlachopoulos C V , Tsioufis K T , Tousoulis D T 
Published: October 2024

Abstract

Background
Leukocyte telomere length (LTL) has been explored as a marker of biological aging, with connections established to age-related diseases like atherosclerosis. Studies have particularly associated telomeres with conditions such as peripheral vascular disease, coronary heart disease, and cardiovascular mortality.

Methods
In this cross-sectional analysis we enrolled individuals from "Corinthia" study which was conducted in the homonym region in Greece. We measured LTL in individuals to obtain comparative metrics on the prevalence of cardiovascular risk factors as well as arterial stiffness. Carotid-femoral pulse wave velocity (cfPWV) was used to evaluate arterial stiffness.

Results
Our analysis included 419 individuals aged 62.4 ± 11.8 years with a median LTL at 6.78 (IQR: 5.08-8.72) bp. Using the median LTL as a cutoff, the cohort was divided into two groups, Group A: 208 patients with low LTL, Group B: 211 patients with high LTL. Group A exhibited a significantly higher proportion of males (52.4% vs. 34.1%, p &lt; 0.01), higher body mass index (BMI) (29.3 ± 4.7 kg/m2 vs. 28.5 ± 4.4 kg/m2, p &lt;0.05), and a higher prevalence of hypertension (78.8% vs. 67.8%, p = 0.01) and dyslipidemia (51% vs. 38.9%, p = 0.014). No significant difference was observed regarding the prevalence of diabetes mellitus, smoking habits, and established cardiovascular disease. In the analysis of the whole cohort, cfPWV was found significant higher in Group A (9.61 ± 3.46 m/s vs. 8.38 ± 2.49 m/s, p &lt;0.01) compared to group B (Figure, Panel A). This association remained significant (β = -0.096, p = 0.038), even after adjustment for confounders in the multivariate regression analysis. Finally, a statistically significant negative correlation between LTL and cfPWV was observed (Figure, Panel B).

Conclusion
LTL plays a pivotal role in cardiovascular health, and lower LTL is associated with impaired cfPWV values and a heightened prevalence of obesity, hypertension, and dyslipidemia.Asociation of LTL with cfPWV values.
Beyond LDL-cholesterol: effects of alirocumab on the human apolipoproteome
Authors: Schmidt L , Theofilatos K , Losdat S , Lang I , Raeber L , Mayr M 
Published: October 2024

Abstract

Introduction
The PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) trial enrolled 300 participants with longitudinal plasma samples available at four time points (enrollment, 24 hours, 4 weeks, 52 weeks), of which 266 completed the 52-week follow-up.

Purpose
Expanding on a previous investigation employing apolipoprotein proteomics in patients with coronary heart disease, the current study aimed to evaluate the impact of the monoclonal antibody alirocumab on apolipoprotein and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.

Methods
A mass spectrometry assay was employed to quantify 15 apolipoproteins. Linear mixed-effects models assessed the impact of timepoints and treatments (alirocumab: n = 131, placebo: n = 135, in addition to statins) on apolipoprotein levels.

Results
Alirocumab led to a fast rise in PCSK9 levels, with a marked increase [inter-quartile range] of 262% [207%] as early as 24 hours after treatment initiation, followed by more pronounced elevations at 4 weeks and 52 weeks, reaching 1575% [813%] and 1480% [747%], respectively (P &lt; 0.001 for all comparisons). At 52 weeks, the ApoB reduction compared with enrollment was -75% [10%] with alirocumab vs. -43% [19%] with placebo (P &lt; 0.001, between groups), while the change in LDL-C was -88% [9%] with alirocumab vs. -54% [19%] with placebo (P &lt; 0.001). Alongside significantly greater reductions in ApoC2 (P = 0.0041) and ApoC3 (P &lt; 0.001) with alirocumab, ApoE changed by -41.6% [21.1%] with alirocumab compared to -15.4% [24.5%] with placebo (P &lt; 0.001). Overall, there was no impact on Apo(a) levels compared to baseline.

Conclusion
The rapid increase in PCSK9 levels after 24 hours suggests immediate immunocomplex formation. A compensatory rise in PCSK9 production may contribute to later elevations. Alirocumab not only lowered LDL-C but also achieved a sustained reduction in very low-density lipoprotein-associated apolipoproteins (ApoC2, ApoC3, and ApoE), indicating additional benefits of PCSK9 inhibitors.
Macrophages overexpressing interleukin-10 target and prevent atherosclerosis: regression of plaque formation and reduction in necrotic core
Authors: Wang M , Zhou S , Zhang L , Chen Y 
Published: October 2024

Abstract

Background
Atherosclerosis, a slowly progressing inflammatory disease, is characterized by the presence of monocyte-derived macrophages. Interventions targeting the inflammatory characteristics of atherosclerosis hold promising potential. Although interleukin (IL)-10 is widely acknowledged for its anti-inflammatory effects, systemic administration of IL-10 has limitations due to its short half-life and significant systemic side effects.

Purpose
We aimed to investigate the effectiveness of an approach designed to overexpress IL-10 in macrophages and subsequently introduce these genetically modified cells into ApoE-/- mice to promote atherosclerosis regression.

Methods
We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirusvectors. The ApoE-/- mice were divided into two groups based on the timing of the intervention. The early intervention group (n = 45) received intravenous tail injections from the beginning of Western diet (WD) at six weeks old. The late intervention group (n = 45) started receiving injections at 16 weeks old, 2 months after being fed the WD. Both the early and late intervention group stopped receiving injections after 5 months of being fed the WD.

Results
The IL-10M exhibited robust IL-10 secretion, maintained phagocytic function, improved mitochondrial membrane potentials, reduced superoxide production and showed a tendency toward the M2 phenotype when exposed to inflammatory stimuli. IL-10M can selectively target plaques in ApoE-/- mice, and oil red staining of the entire aorta unequivocally demonstrated that intervention with IL-10M elicited a substantial reduction in plaque area. H&E staining revealed that mice treated with IL-10M in the early intervention group showed a significant reduction in the ratio of plaque area to lumen area. However, the late intervention group did not exhibit statistically significant differences. Notably, mice treated with IL-10M exhibited significantly smaller necrotic cores and reduction in matrix metalloproteinase 9 within the aortic plaques in both the early and late intervention groups. Additionally, the administration of IL-10M showed no obvious side effects.

Conclusion
We developed an anti-inflammatory protein delivery system based on engineered macrophages that can target atherosclerotic plaques and reduce the plaque area and necrotic core. This approach has a promising safety profile and has the potential to be a therapeutic strategy for the intervention of atherosclerosis.
Valvular leaflets and epicardial fat have a significant effect on lesion size in RF ablation
Authors: Colling C C , Reents T R , Kottmaier M K , Englert F , Bahlke F , Deisenhofer I , Bourier F 
Published: October 2024

Abstract

Introduction
Radiofrequency (RF) current is the classic ablation technology in the EP lab. Underlying RF ablation parameters, such as RF power, impedance, duration and contact force are used to calculate expected lesion size. Furthermore, lesion indices (LSI, AI) are applied to estimate expected lesion durability and contiguity.

Purpose
The aim of this ex-vivo study was to assess the influence of valvular tissue and epicardial fat on RF lesion creation.

Methods
An ex-vivo porcine model was created to create RF lesions under standardized conditions. Temperature was constantly kept at 37°C using a thermostat and a circulation pump was used to imitate blood flow. A contact force sensing ablation catheter (ST SF) was used to create RF lesions using predefined RF parameters (30W/50W, CF 10g, 30sec). Lesions using the same RF parameters were created above and right next to mitral valve leaflets as well as on epicardial fat tissue (figure 1). Lesions were then dissected, and lesion depths and diameters were measured using a digital precision caliper.

Results
A total of 210 lesions were created. RF lesions ablated on valvular leaflets showed significantly smaller lesion depth and lesion diameter when compared to RF lesions ablated right next to valvular (diameter 8.0±2.0mm vs 10.8±1.8mm; depth 4.4±1.2 vs 7.7±1.6mm, p&lt;0.01). Lesions ablated on epicardial fat were significantly smaller in diameter (9.2±1.5) and depth (6.5±1.8) than purely endocardial lesions (p&lt;0.01). Examples are depicted in figure 1.

Conclusions
Valvular leaflets as well as epicardial fat tissue have a significant influence on RF lesion creation. RF ablation performed on valvular leaflets or epicardial fat results in significantly (p&lt;0.01) smaller lesions when compared to RF ablations directly on endocardial tissue. This should be considered in ablations of accessory pathways and epicardial procedures.Figure 1
Left atrial substrate modification for persistent atrial fibrillation and left atrial macro or microreentrant tachycardia using a single-shot pulsed field ablation system - a single centre case series
Authors: Lustig P , Lee J , Sponder M , Stix G , Hengstenberg C , Schoenbauer R , Stojkovic S 
Published: October 2024

Abstract

Background
Pulsed field ablation (PFA) is a novel ablation technique for pulmonary vein isolation (PVI) in patients with paroxysmal and persistent atrial fibrillation. However, data for efficacy and safety of PFA for left atrial substrate modification in patients with long-standing persistent atrial fibrillation (AF) and macro- as well as microreentrant atrial tachycardia (AT) is scarce.

Aim
Here we provide a retrospective, single-centre case series regarding efficacy and safety of left atrial substrate modification, using a single-shot PFA system.

Methods and Results
Over a period of 6 months, 8 patients with long-standing persistent AF and AT underwent Re-PVI with left atrial substrate modification using a single-shot PFA system. Median age was 63 years (IQR 58 - 75), and 4/8 of patients were female. Time from first diagnosis of AF was 7 years (IQR 4 –10). All but 1 patient underwent previous PVI (IQR 1-3) with (5/7) or without (2/7) prior substrate modification using radiofrequency ablation. On transthoracic echocardiography, all patients showed severe left- and right-atrial enlargement, with LA volume of 58 ml/m2 (IQR 49.7–72) and RA diameter of 62 mm (IQR 55-75). In 8 patients, 9 ATs and 2 typical flutters were treated with PFA. Following PVI, additional posterior wall isolation was performed in 6/8 patients, roof in 6/8, and anterior wall (between superior mitral anulus and RSPV) in 4/8 patients. In addition, 2/8 patients had cavotricuspid isthmus ablation for typical atrial flutter. All patients received atropine prior to PVI, as well as bolus of nitro-glycerine prior to PFA of anterior wall and/or cavotricuspid isthmus. Acute success rate was 100% and all ATs as well as typical flutter terminated with PFA. After median follow-up time of 88 days (IQR 61-112), 3 patients had a documented recurrence of AF/AT, in 2 of which electrical cardioversion was necessary. We observed no acute and/or chronic complications following PFA, i.e. no pericardial effusion/tamponade, TIA/stroke, myocardial infarction, coronary artery spasm, AV-block, bleeding, or atrioesophageal fistula.

Conclusion
In this small, single-centre case series, left atrial substrate modification for long-standing persistent AF and AT using a single-shot PFA system was safe and showed an excellent acute success rate.
Association between preprocedural thromboembolic or bleeding events under oral anticoagulation therapy and mid-term outcomes after percutaneous left atrial appendage closure
Authors: Sumiyoshi H , Fujita M , Nishiura N , Mushiake K , Chatani R , Ono S , Tasaka H , Maruo T , Kadota K , Kubo S 
Published: October 2024

Abstract

Background
Currently, no consensus has been established on the most effective antithrombotic therapy to prevent thromboembolic and bleeding events in patients undergoing percutaneous left atrial appendage closure (LAAC).

Methods
We retrospectively investigated the incidence of device-related thrombosis (DRT), thromboembolic events, and bleeding events in patients who underwent LAAC from September 2019 to October 2022. After categorizing patients into groups based on preprocedural thromboembolic or bleeding events under oral anticoagulation (OAC) therapy, we compared the incidence of DRT and prognosis according to the postprocedural antithrombotic therapy.

Results
In patients who received the conventional antithrombotic therapy (OAC with and without single antiplatelet therapy for 45 days after LAAC and dual-antiplatelet therapy from 45 days to 6 months followed by single antiplatelet therapy), preprocedural thromboembolic events despite OAC were independently associated with DRT or postprocedural thromboembolic events at the 3-year follow-up (hazard ratio [HR] 4.55; 95% confidence interval [CI] 1.32–15.6; P = 0.016), whereas preprocedural bleeding events were independently associated with postprocedural bleeding events (HR 8.01, 95% CI 1.45–58.3; P = 0.036). Continuation of OAC for 12 months among patients who developed preprocedural thromboembolic events during OAC significantly decreased the incidence of DRT or postoperative thromboembolic events (P = 0.002) with no increase in the bleeding events (P = 0.522).

Conclusions
Preprocedural thromboembolic and bleeding events can predict adverse events after LAAC with conventional antiplatelet-based antithrombotic therapy. Patients who develop thromboembolic events under continuous OAC may benefit from continuous OAC for 1 year after LAAC.
Remote monitoring of cardiac implantable electronic devices using smart device interface versus radiofrequency-based interface: a systematic review
Authors: See Tow H , Fong K Y , Wang Y , Yeo C , Ching C K , Lim T W , Tan V H 
Published: October 2024

Abstract

Background
Guidelines recommended remote monitoring (RM) in managing patients with Cardiac Implantable Electronic Devices (CIED). In recent years, smart device (phone or tablet) monitoring-based RM (SM-RM) was introduced. SM-RM is a specifically developed application (app) which can be downloaded from app stores using smart devices. The app uses Bluetooth low-energy to communicate automatically and securely with the patient’s CIED. The app then uses a cellular or Wi-Fi internet connection to transfer the data securely to the manufacturer’s repository.

Purpose
This study aims to systematically review SM-RM versus bedside monitor RM (BM-RM) using radiofrequency in terms of compliance, connectivity, and episode transmission time.

Methods
We conducted a systematic review, searching three international databases from inception until July 2023 for studies comparing SM-RM (intervention group) versus BM-RM (control group).

Results
Two propensity score-matched studies with a total of 21978 patients were retrieved (9642 patients in the SM-RM arm and 12336 patients in the BM-RM arm) (1, 2). There is significantly higher compliance among patients using SM-RM compared with patients using BM-RM in both pacemaker and defibrillator patients. There were higher enrolment rates and completed scheduled transmissions among SM-RM compared to BM-RM. Higher connectivity was also seen in patients with SM-RM, and more SM-RM patients transmitted at least once compared to BM-RM patients. Additionally, SM-RM patients had more patient-initiated transmissions compared to BM-RM patients. Younger patients (aged &lt;75) had more patient-initiated transmissions, and a higher proportion had ≥10 such transmissions compared with older patients (aged ≥75) in both SM-RM and BM-RM groups. The episode transmission time of SM-RM patients was also shorter than that of BM-RM patients.

Conclusion
SM-RM is a step in the right direction, with good compliance, connectivity, and shorter episode transmission time. It allows patients to feel empowered and in control of their health. Further research on cost-effectiveness and long-term clinical outcomes can be carried out in the future.
Eight year Follow-Up Data on a Leadless Pacing System Real life experience in comparison to data of the prospective trial
Authors: Winter S , Nguyen Q , Tuscher T , Fischer S , Sinning J M 
Published: October 2024

Abstract

Introduction
The Micra leadless intracardiac pacing system has been introduced and implemented into clinical routine in 2015, with its next generation MICRA AV in 2020. Feasibility, implantation safety, and acute success have been proven in the setting of controlled studies. Even apart from controlled studies, this new technology was beneficial for the individual patient. We aimed to report our single center follow-up (FU) data with a follow-up of up to six years.

Methods
In 292 patients (146 men; age: 81±5,7 y), Micra implantation was performed.
Pacemaker interrogation was performed one to seven days after implantation and during FU (1; 3; 6, then every 6 month) up to 84 months. Data were assessed in a real-life setting and compared with existing data of a controlled prospective trial.

Results
The implantation was successful in all 292 attempts with only one pericardial effusion as major complication. During follow up there were two patients developing severe heart failure symptoms resulting in an implantation of a CRT-device and switching of the leadless pacemaker system.
The average acute thresholds, sensing and impedance after system release were: 0.57±0.34V@0.24ms; 10,02±3,96mV and 752±1201Ohm. During follow up of up to 8 years neither, pacemaker failure, nor infections were reported. Measurements were reevaluated for long-term thresholds, sensing and impedance: 0.75 ± 0.38V @ 0.24 ms; 18,38 ±2,75 mV and 525 ± 102 Ohm. During eight years, no significant changes from acute to long-term measurements were detectable. In comparison to the controlled trial, our measurements of this real-life cohort were very similar.

Conclusion
In a real-life setting, the implantation of the leadless Micra system demonstrates a high rate of implantation success without major complications. We were also able to show stable long-term system parameters in the clinical setting of up to seven years of follow up with a very good battery longevity of about 12,3 years.
Equal performance of the subcutaneous and transvenous implantable cardioverter defibrillator across all age groups in the PRAETORIAN trial
Authors: Pepplinkhuizen S , Olde Nordkamp L R A , Kuschyk J , Bonnemeier H , El-Chami M F , De Weger A , Van Der Stuijt W , Smeding L , Bijsterveld N R , Richter S , Boersma L V A , Betts T R , Wilde A A M , Knops R E 
Published: October 2024

Abstract

Introduction
The subcutaneous ICD (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. In the PRAETORIAN trial the S-ICD proved to be non-inferior to the TV-ICD with regard to inappropriate shocks (IAS) and complications. However, the S-ICD is still mainly the preferred choice in young patients with a long life expectancy and therefore higher risk for lead-related complications. We aimed to evaluate the impact of age on complications and IAS between the S-ICD and TV-ICD.

Methods
The PRAETORIAN trial is an investigator-initiated, international, multicenter, randomized, two-arm noninferiority trial that was conducted in the United States and Europe. In total 849 patients with a class I or IIa indication for ICD therapy and no pacing indication were randomized to receive an S-ICD (N=426) or TV-ICD (N=423) and followed for a median of 49 months. We compare the occurrence of complications and IAS between increasing quartiles of age.

Results
Quartile 1 (Q1) consisted of 203 patients aged &lt;55 (109 S-ICD, 94 TV-ICD), Q2 of 199 patients aged 55-62 (100 S-ICD, 99 TV-ICD), Q3 of 232 patients aged 63-69 (111 S-ICD, 121 TV-ICD) and Q4 of 215 patients aged ≥70 (106 S-ICD, 109 TV-ICD). Between the quartiles, there were no significant differences in occurrence of device-related complications (P = 0.32) or IAS (P = 0.66). In Q1, there were 15 (7.4%) complications (5 S-ICD, 10 TV-ICD) and 13 (6.4%) IAS (7 S-ICD, 6 TV-ICD), compared to 20 (10.1%) complications (7 S-ICD, 13 TV-ICD) and 17 (8.5%) IAS (9 S-ICD, 8 TV-ICD) in Q2, 22 (9.5%) complications (12 S-ICD, 10 TV-ICD) and 19 (8.2%) IAS (11 S-ICD, 8 TV-ICD) in Q3 and 18 (8.4%) complications (7 S-ICD, 11 TV-ICD) and 21 (9.8%) IAS (14 S-ICD, 7 TV-ICD) in Q4 (Figure 1.). Figure 2. shows forest plots of the hazard ratios per quartile.

Conclusions
The S-ICD performed equal to the TV-ICD with regard to IAS and complications between quartiles of age, making the S-ICD a good alternative across all age groups.