Atrial High-Rate Episodes and Subclinical Atrial Fibrillation: State of the Art and Clinical Questions with Complex Solutions.

Atrial high-rate episodes (AHREs) and subclinical atrial fibrillation (AF) are frequently registered in asymptomatic patients with cardiac implantable electronic devices (CIEDs) and insertable cardiac monitors (ICMs). While an increased risk of thromboembolic events (e.g., stroke) and benefits from anticoagulation have been widely assessed in the setting of clinical AF, concerns persist about optimal clinical management of subclinical AF/AHREs. As a matter of fact, an optimal threshold of subclinical episodes' duration to predict stroke risk is still lacking and recently published randomized clinical trials assessing the impact of anticoagulation on thromboembolic events in this specific setting have shown contrasting results. The aim of this review is to summarize current evidence regarding classification and clinical impact of subclinical AF/AHREs and to discuss the latest evidence regarding the potential benefit of anticoagulation in this setting, highlighting which clinical questions are still unanswered.

Statins during Anticoagulation for Emergency Life-Threatening Venous Thromboembolism: A Review.

Venous thromboembolism (VTE) is the leading cause of morbidity and death worldwide, after cancer and cardiovascular diseases. VTE is defined to include pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Approximately 25% of PE patients experience sudden death as an initial symptom of VTE, and between 10% and 30% of patients die within the first month after diagnosis. Currently, the only drugs approved for the treatment of both acute and chronic VTE are vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). However, their effectiveness is limited due to their associated risk of bleeding. Ideally, therapy should be able to treat VTE and limit the risk of VTE recurrence without increasing the risk of bleeding. Several studies have shown that the use of statins during anticoagulation for VTE reduces the risk of death and VTE recurrence. However, to date, there are conflicting data on the impact of statins during anticoagulation for VTE. A biological protective function of statins during anticoagulation has also been reported. Statins affect D-dimer levels; tissue factor (TF) gene expression; and VIII, VII, and Von Willebrand clotting factors-the major clotting factors they are able to affect. However, the usefulness of statins for the treatment and prevention of VTE is currently under debate, and they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment. In this review of the literature, we illustrate the advances on this topic, including data on the role of statins in primary VTE prevention and secondary VTE prevention, related biological mechanisms, the risk of bleeding during their use, and their ability to reduce the risk of death.

The triggers of situational syncope do not influence the head-up tilt test response and prognosis.

AIMS: The study evaluated the positivity rate, haemodynamic responses, and prognosis in terms of syncopal recurrence among patients with situational syncope (SS) stratified according to the underlying situational triggers. METHODS AND RESULTS: We retrospectively evaluated all consecutive patients with SS who underwent nitroglycerine (NTG)-potentiated head-up tilt test (HUTT) at Syncope Unit of the University of Campania 'Luigi Vanvitelli'-Monaldi Hospital from 1 March 2017 to 1 May 2023. All patients were followed for at least one year. The study population was divided according to the underlying triggers (micturition, swallow, defaecation, cough/sneeze, post-exercise). Two hundred thirty-six SS patients (mean age 50 ± 19.3 years; male 63.1%) were enrolled; among them, the situational trigger was micturition in 109 patients (46.2%); swallow in 32 (13.6%) patients; defaecation in 35 (14.8%) patients; post-exercise in 41 (17.4%) patients; and cough/sneeze in 17 (7.2%) patients. There were no significant differences in baseline clinical characteristics and HUTT responses between different situational triggers. The Kaplan-Meier analysis did not show a statistically different rate of syncope recurrence across patients stratified by baseline situational triggers (log-rank P = 0.21). CONCLUSION: Situational syncope appears to be a homogenous syndrome, and different triggers do not impact the HUTT response or syncope recurrence at 1 year.

Bacterial Porins and Their Procoagulant Role: Implication in the Pathophysiology of Several Thrombotic Complications during Sepsis.

The association between sepsis and thrombotic complications is still not well known. Different mechanisms have been shown to be involved in the sepsis-induced prothrombotic state, but clinical scenarios may differ. In this review, we have summarized the role that bacterial products such as porins and toxins can have in the induction of the prothrombotic state during sepsis and the interaction that they can have with each other. Furthermore, the above-mentioned mechanisms might be involved in the pattern of the clinical presentation of thrombotic events during bacterial sepsis, which would secondarily explain the association between sepsis and venous thromboembolism, the association between sepsis and disseminated intravascular coagulation, and the association between sepsis and microangiopathic venous thromboembolism.

Development, optimization and ex-vivo evaluation of a transdermal formulation containing trazodone.

Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.

Insulin-Heart Axis: Bridging Physiology to Insulin Resistance.

Insulin signaling is vital for regulating cellular metabolism, growth, and survival pathways, particularly in tissues such as adipose, skeletal muscle, liver, and brain. Its role in the heart, however, is less well-explored. The heart, requiring significant ATP to fuel its contractile machinery, relies on insulin signaling to manage myocardial substrate supply and directly affect cardiac muscle metabolism. This review investigates the insulin-heart axis, focusing on insulin's multifaceted influence on cardiac function, from metabolic regulation to the development of physiological cardiac hypertrophy. A central theme of this review is the pathophysiology of insulin resistance and its profound implications for cardiac health. We discuss the intricate molecular mechanisms by which insulin signaling modulates glucose and fatty acid metabolism in cardiomyocytes, emphasizing its pivotal role in maintaining cardiac energy homeostasis. Insulin resistance disrupts these processes, leading to significant cardiac metabolic disturbances, autonomic dysfunction, subcellular signaling abnormalities, and activation of the renin-angiotensin-aldosterone system. These factors collectively contribute to the progression of diabetic cardiomyopathy and other cardiovascular diseases. Insulin resistance is linked to hypertrophy, fibrosis, diastolic dysfunction, and systolic heart failure, exacerbating the risk of coronary artery disease and heart failure. Understanding the insulin-heart axis is crucial for developing therapeutic strategies to mitigate the cardiovascular complications associated with insulin resistance and diabetes.

Continuous Rhythm Monitoring With Implanted Loop Recorders in Children and Adolescents With Brugada Syndrome.

BACKGROUND: Young (<18 years of age) patients with Brugada syndrome (BrS) are often under-represented in BrS studies and their management, especially related to syncopal episodes, remains unclear. OBJECTIVES: This study sought to describe the arrhythmia prevalence among young patients with BrS undergoing continuous rhythm monitoring by implantable loop recorder (ILR) and to assess the etiology behind syncope of undetermined origin. METHODS: A total of 147 patients with BrS with ILR were enrolled in 12 international centers and divided into pediatric (age <12 years; n = 77, 52%) and adolescents (age 13-18 years; n = 70, 48%). RESULTS: Mean age was 11.3 years, 53 patients (36.1%) were female, and 31 (21.1%) had spontaneous type 1 electrocardiograms. Over a median follow-up of 3.6 years (Q1-Q3: 1.6-4.8 years), an arrhythmic event was recorded in 33 patients (22.4%), mainly of nonventricular origin: 15 atrial (10.2%) and 16 bradyarrhythmic events (10.9%). Ventricular arrhythmias occurred in 4 patients, all with spontaneous BrS, and were fever-related in one-half. Among all patients with recurrence of syncope during follow-up, true arrhythmic syncope was documented in 5 (17.8%), and it was due to bradyarrhythmias or atrial arrhythmias in 3 cases (60%). CONCLUSIONS: Continuous rhythm monitoring with ILRs in young patients with BrS detects a broad range of arrhythmias. Ventricular arrhythmias occur predominantly in patients with spontaneous type 1 electrocardiograms and during fever. Despite the young age, bradyarrhythmias and atrial arrhythmias are frequent and represent the cause of arrhythmic syncope in 60% of patients. Young patients with BrS with syncope of undetermined origin may benefit from ILR implant.

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling.

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Takotsubo Syndrome Associated with Neurally Mediated Reflex Syncope: A Meta-summary of Case Reports and Literature Review.

Background: Neurally mediated reflex syncope (NMRS) has been recently described as a possible trigger of Takotsubo syndrome (TTS). There are few data in the literature about this association. Methods: In the present meta-summary, 6 case reports describing patients who experienced TTS following an NMRS episode were included. Patient characteristics, triggers and type of syncope were collected. Results: A total of 7 patients with a median age of 63.4 years (interquartile range, IQR: 47.5-76) were evaluated; 71.4% were females, mainly in the menopausal state (80%). The TTS triggers were: vasovagal syncope in 6 patients (85.7%) and situational syncope in 1 patient (14.3%). 2 patients underwent a comprehensive clinical evaluation which showed a cardioinhibitory response. Conclusions: NMRS due to sudden orthostatism and emotional stress, mainly with a cardioinhibitory response, has been associated with the onset of TTS, in particular among female patients in a menopausal state.

Clinical Performance and Persistence on Dual Pathway Inhibition with Rivaroxaban and Aspirin in Real-World Setting.

ABSTRACT: The dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease reduces the occurrence of cardiovascular events, with no significant increase of intracranial or other critical organ bleedings. Our observational study aimed to describe the clinical performance, adherence, and persistence of DPI therapy among a real-world setting of patients with an established diagnosis of coronary artery (CAD) and/or peripheral artery disease (PAD). We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin (ASA) 100 mg once daily and rivaroxaban 2.5 mg twice daily. Clinical evaluation was performed at baseline, before starting treatment, at 1 month, and every 6 months after the study drug administration. A total of 202 consecutive patients (mean age 66 ± 10 years; male 80%) eligible to DPI therapy were included. During a mean follow-up of 664 ± 177 days, the incidence rate of major bleedings and of major adverse cardiovascular events was 0.8 and 1.1 per 100 patients/year, respectively. The adherence to pharmacological treatment was 99%. Additionally, 13.4% of patients suspended the DPI therapy during the follow-up. Minor bleedings resulted the most common cause of both temporary and permanent DPI therapy discontinuation. This observational study supports the safety of DPI with low-dose rivaroxaban and aspirin among patients with CAD and PAD in a real-world setting, showing high persistence and maximum adherence to medical treatment.

Commentary on Anti-thrombotic effect of protoparaxotriol saponins from Panax notoginseng using zebrafish model.

Thrombosis continues to pose a significant challenge in cardiovascular and cerebrovascular diseases, contributing to severe health complications such as myocardial infarction, acute ischemic stroke, and venous thromboembolism. Despite the wide array of anti-thrombotic drugs available, these treatments frequently carry substantial risks, notably including bleeding complications. In this paper, we comment the findings reported by Liu et al. about the anti-thrombotic potential of protopanaxatriol saponins from panax notoginseng.

Prevalence and clinical predictors of vasodepressor syncope during head up tilt test.

INTRODUCTION: The aim of our study was to evaluate the prevalence and clinical predictors of vasodepressor (VD) response during head-up tilt test (HUTT) in patients with history of syncope admitted to a tertiary referral syncope unit. MATERIAL AND METHODS: We retrospectively evaluated all consecutive patients who underwent HUTT for suspected or established reflex syncope at our institution from March 1st, 2017, to June 1st, 2023. VD response was defined when syncope occurred during hypotension along with no or slight (< 10% bpm) decrease of heart rate. Univariate and multivariate analyses were performed to test the association of VD response to HUTT with a set of clinical covariates. RESULTS: 1780 patients (40 ± 19.9 years; 49.3% male) were included; among them, 1132 (63 %) showed a positive response to HUTT and 124 (7.0%) had a VD response. The prevalence of VD response showed a peak after 69 years (11.52% vs 6.18%; P = 0.0016), mainly driven by male patients (13.7% vs 4.9%; P < 0.0001). At multivariate analysis, age (OR: 1.15; P = 0.0026) was independently associated to HUTT-induced VD syncope; in contrast, smoking (OR: 0.33: P = 0.0009) and non-classical presentation of syncope (OR: 0.55; P = 0.0029) inversely correlated with VD syncope. CONCLUSIONS: VD response represents the less frequent responses among those induced by HUTT, accounting up to 7% of overall responses. A gender and age-related distribution has been shown. Advanced age was the only independent predictor of VD syncope; conversely, smoking and non-classical presentation of syncope reduced the probability of VD response to HUTT.

Migration of long-sensing vector implantable loop recorder unmasked by remote monitoring in patient with unexplained syncope.

A 75-year-old man with hypertrophic obstructive cardiomyopathy underwent placement of a long-sensing vector implantable loop recorder (ILR) for unexplained syncope. One month later, ILR remote monitoring revealed unstable R-wave amplitudes ranging from very high (>1.9 mV) to very low (<0.2 mV) values. During an in-hospital clinic visit, the only site to establish communication with the ILR was the left posterior axillary area. Chest computed tomography confirmed ILR migration into the anterior costophrenic recess. The device was retrieved with forceps during video thoracoscopy without further complications. Learning objective: This is the first case report of migration of an implantable loop recorder diagnosed by remote monitoring.

Selection of candidates for cardiac resynchronization therapy and implantation management: an Italian survey promoted by the Italian Association of Arrhythmology and Cardiac Pacing.

BACKGROUND: Cardiac resynchronization therapy (CRT) represents an effective heart failure treatment, associated with reduction in mortality and heart failure hospitalizations. This Italian survey aimed to address relevant CRT issues. METHODS: An online survey was administered to AIAC members. RESULTS: One hundred and five electrophysiologists participated, with a median of 40 (23-70) CRT implantations/year (33% in high-volume centres). Forty-five percent of respondents (especially working in high-volume centres) reported an increase in CRT implantations in the last 2 years, in 16% a decrease, and in 38% CRT remained stable. Seventy-five percent of respondents implanted CRT only in patients with European Heart Rhythm Association (EHRA) class I indications. All operators collected ECG and echocardiography before implantation. Eighty-five percent of respondents selected coronary sinus target vein empirically, whereas 10% used mechanical and/or electrical delay techniques. Physicians working in high-volume centres reported a lower failure rate compared with others (16 vs. 34%; P = 0.03). If the coronary sinus lead could not be positioned in the target branch, 80% placed it in another vein, whereas 16% opted for a surgical approach or for conduction system pacing (CSP). Eighty percent accomplished CRT optimization in all patients, 17% only in nonresponders. Regarding anticoagulation, high agreement with EHRA guidelines emerged. CONCLUSION: CRT represents a valid therapeutic option in heart failure treatment. Nowadays, CRT implantations remain stable and are mainly performed in patients with class I indications. ECG remains the preferred tool for patient selection, whereas imaging is increasingly used to determine the left pacing target area. In most patients, the left ventricular lead can be successfully positioned in the target vein, but in some cases, the result can be unsatisfactory; however, the decision to explore alternative resynchronization approaches is rarely pursued.

Synthesis of new defoamer agents and characterization of cementitious formulations.

The production of cementitious formulations involves the addition of chemical additives essential for the optimization of many properties. Superplasticizers are considered additives of great interest but when mixed with concrete they lead to an undesirable increase of air content, with the consequent development of foam. This can adversely affect both mechanical properties and workability, therefore, the use of an antifoam agent is also necessary which should be able to prevent or destroy the foam. This work aims to synthesize esters derived from the reaction of glycine betaine with saturated and unsaturated fatty alcohols of different chain lengths. The reaction products were analyzed by 1H NMR analysis, and the stability of antifoam agents in a superplasticizer solution was studied through foaming tests according to the Ross-Miles method. At the same time, their effectiveness in the cementitious systems was evaluated through flow Table tests. Finally, the effectiveness of the antifoam agents was quantified through an image analysis software, Image J, which allowed the investigation of the contents of the bubble in concrete samples. All synthesized antifoams showed properties superior to the commercial product, especially defoamers containing saturated fatty alcohols. It has been found that alcohols with too small or too long carbon chains were not effective. In particular, it was verified the optimal range of carbon atoms number contained in the antifoam chain which included between 12 and 14.

Advances in Nanomedicine for Precision Insulin Delivery.

Diabetes mellitus, which comprises a group of metabolic disorders affecting carbohydrate metabolism, is characterized by improper glucose utilization and excessive production, leading to hyperglycemia. The global prevalence of diabetes is rising, with projections indicating it will affect 783.2 million people by 2045. Insulin treatment is crucial, especially for type 1 diabetes, due to the lack of ß-cell function. Intensive insulin therapy, involving multiple daily injections or continuous subcutaneous insulin infusion, has proven effective in reducing microvascular complications but poses a higher risk of severe hypoglycemia. Recent advancements in insulin formulations and delivery methods, such as ultra-rapid-acting analogs and inhaled insulin, offer potential benefits in terms of reducing hypoglycemia and improving glycemic control. However, the traditional subcutaneous injection method has drawbacks, including patient compliance issues and associated complications. Nanomedicine presents innovative solutions to these challenges, offering promising avenues for overcoming current drug limitations, enhancing cellular uptake, and improving pharmacokinetics and pharmacodynamics. Various nanocarriers, including liposomes, chitosan, and PLGA, provide protection against enzymatic degradation, improving drug stability and controlled release. These nanocarriers offer unique advantages, ranging from enhanced bioavailability and sustained release to specific targeting capabilities. While oral insulin delivery is being explored for better patient adherence and cost-effectiveness, other nanomedicine-based methods also show promise in improving delivery efficiency and patient outcomes. Safety concerns, including potential toxicity and immunogenicity issues, must be addressed, with the FDA providing guidance for the safe development of nanotechnology-based products. Future directions in nanomedicine will focus on creating next-generation nanocarriers with precise targeting, real-time monitoring, and stimuli-responsive features to optimize diabetes treatment outcomes and patient safety. This review delves into the current state of nanomedicine for insulin delivery, examining various types of nanocarriers and their mechanisms of action, and discussing the challenges and future directions in developing safe and effective nanomedicine-based therapies for diabetes management.

Effects of Heart Failure Therapies on Atrial Fibrillation: Biological and Clinical Perspectives.

Heart failure (HF) and atrial fibrillation (AF) are prevalent cardiovascular diseases that contribute significantly to morbidity, mortality, hospitalisation, and healthcare costs. It is not uncommon for these conditions to coexist and have mutually reinforcing effects. A critical factor in the aetiology of these conditions is oxidative stress, driven by reactive oxygen species (ROS), which contributes to atrial remodelling and fibrosis. The recent introduction of new drugs for the treatment of heart failure has also had an impact on the management of atrial fibrillation due to their influence on oxidative stress. The objective of this review is to analyse the effects of these therapies, including their role in mitigating ROS, on the prevention and treatment of AF in HF patients.

From E-Commerce to the Metaverse: A Neuroscientific Analysis of Digital Consumer Behavior.

The growing interest in consumer behavior in the digital environment is leading scholars and companies to focus on consumer behavior and choices on digital platforms, such as the metaverse. On this immersive digital shopping platform, consumer neuroscience provides an optimal opportunity to explore consumers' emotions and cognitions. In this study, neuroscience techniques (EEG, SC, BVP) were used to compare emotional and cognitive aspects of shopping between metaverse and traditional e-commerce platforms. Participants were asked to purchase the same product once on a metaverse platform (Second Life, SL) and once via an e-commerce website (EC). After each task, questionnaires were administered to measure perceived enjoyment, informativeness, ease of use, cognitive effort, and flow. Statistical analyses were conducted to examine differences between SL and EC at the neurophysiological and self-report levels, as well as between different stages of the purchase process. The results show that SL elicits greater cognitive engagement than EC, but it is also more mentally demanding, with a higher workload and more memorization, and fails to elicit a strong positive emotional response, leading to a poorer shopping experience. These findings provide insights not only for digital-related consumer research but also for companies to improve their metaverse shopping experience. Before investing in the platform or creating a digital retail space, companies should thoroughly analyze it, focusing on how to enhance users' cognition and emotions, ultimately promoting a better consumer experience. Despite its limitations, this pilot study sheds light on the emotional and cognitive aspects of metaverse shopping and suggests potential for further research with a consumer neuroscience approach in the metaverse field.