Carotid Sinus Massage in clinical practice: the Six-Step-Method.

Carotid sinus massage (CSM) as integral part of cardiovascular autonomic testing, is indicated in all patients > 40 years with syncope of unknown origin and suspected reflex mechanism. However, large practice variation exists in performing CSM which inevitably affects the positivity rate of the test and may result in an inaccurate diagnosis in patients with unexplained syncope. Even though CSM was introduced into medical practice more than 100 years ago, the method of performing CSM is still largely operator- and centre-dependent, while in many places the test has been entirely abandoned. Here we describe a standardized protocol on how to perform CSM, which basic monitoring equipment is necessary and why CSM is a safe procedure to perform. Our aim is to create an uniform approach to perform CSM. The new proposed algorithm, the Six Step Method includes: 1) Check history for exclusion CSM; 2) Turn head slightly contralaterally and posterior (see also explanatory video and poster provided as supplementary material; 3) Palpation to identify carotid sinus location; 4) Massage for 10 seconds; 5) Monitoring of blood pressure and heart rate to assess of the hemodynamic response type, and 6) Include time intervals between subsequent massages. CSM should be performed on both the left and right and in the supine and upright position. The recommended equipment to perform CSM consists of: 1) a tilt table in order to perform CSM in supine and standing position, 2) a continuous blood pressure monitor or cardiac monitor and 3) at least two persons.

Recovery of cardiovascular diagnostic testing in Italy 1 year after coronavirus disease-2019 outbreak compared with other countries in Europe and worldwide: results from the International Atomic Energy Agency INCAPS COVID 2 survey.

Aims: Recovery of cardiovascular diagnostic testing in Italy after the coronavirus disease-2019 (COVID-19) pandemic has not been quantified. The study aims to describe cardiac diagnostic procedure volumes, centres practice and protocols, and staff members' well-being 1 year after COVID-19 outbreak in Italy. Methods and results: A global survey was conducted by the International Atomic Energy Agency to evaluate changes in cardiac diagnostic procedure volumes in April 2021. Evaluated procedures were transoesophageal echocardiogram, coronary computed tomography angiography, coronary artery calcium scanning, nuclear medicine infection studies, invasive coronary angiography, rest and stress transthoracic echocardiogram, cardiac magnetic resonance, single-photon emission computed tomography and positron emission tomography, and stress electrocardiogram. Data were compared with April 2020 and March 2019. Forty-two Italian centres took part in the survey. In April 2020, there was a 72% decrease of median volumes of cardiac diagnostic procedures compared with March 2019. In April 2021, volumes of cardiac diagnostic procedures remained decreased by 3% when compared with March 2019. Stress electrocardiogram, coronary computed tomography angiography, and stress cardiac magnetic resonance volumes increased in April 2021 compared with baseline (29%, 6%, and 16%, respectively). The majority of centres had adopted physical distancing measures (93%), COVID-19 screening through questionnaires (76%), or temperature checks (93%). Twenty-five per cent of physicians at Italian responding sites reported excessive levels of psychological stress. Conclusion: In April 2021, volumes of cardiac diagnostic procedures at Italian responding sites were still recovering. Centres had implemented several adaptations to ensure the provision of care to their patients. Even 1 year after the pandemic, a substantial minority of Italian healthcare providers were still experiencing excessive psychological stress.

The coronavirus disease-2019 pandemic has had an impact on cardiovascular care provision, leading to a decrease in the number of diagnostic procedures performed. As of April 2021, volumes of cardiovascular diagnostic procedures in Italy were still recovering, despite the implementation of several adaptations by healthcare centres to deal with the pandemic.

Prognostic significance of electrophysiological study in drug-induced type-1 Brugada syndrome: a brief systematic review.

BACKGROUND: Risk stratification in drug-induced type-1 Brugada syndrome (BrS) patients is challenging. The role of electrophysiological study (EPS) is debated as the majority of drug-induced type-1 BrS patients would not be studied according to the latest recommendations. METHODS: A complete systematic literature search was performed to gauge the EPS role in this population. Three subgroups were defined: positive-EPS group, negative-EPS group, no-EPS group. RESULTS: Among 1318 drug-induced type-1 BrS patients, no significant difference in the incidence rate of arrhythmic events was observed between groups (I2 = 45%, P for subgroup difference = 0.10) during a mean follow-up of 5.1 years, also considering symptomatic status. CONCLUSION: In long-term follow-up of drug-induced type-1 BrS patients, EPS does not seem to aid prognostic stratification.

Advances in the Insulin-Heart Axis: Current Therapies and Future Directions.

The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.

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.

Echocardiography in Cardiac Arrest: Incremental Diagnostic and Prognostic Role during Resuscitation Care.

BACKGROUND: Cardiac arrest (CA) is a life-critical condition. Patients who survive after CA go into a defined post-cardiac arrest syndrome (PCAS). In this clinical context, the role of the echocardiogram in recent years has become increasingly important to assess the causes of arrest, the prognosis, and any direct and indirect complications dependent on cardiopulmonary resuscitation (CPR) maneu-vers. METHODS: We have conduct a narrative revision of literature. RESULTS: The aim of our review is to evaluate the increasingly important role of the transthoracic and transesophageal echocardiogram in the CA phase and especially post-arrest, analyzing the data already present in the literature. CONCLUSION: Transthoracic and transesophageal echocardiogram in the CA phase take on important diagnostic and prognostic role.

Valorization of Iron (II) Oxalate Dihydrate Coming from Pickling Processes through Thermal Conversion.

The valorization of industrial byproducts is an emerging practice that aims to transform waste materials generated during production processes into valuable resources. In this work, a preliminary study was carried out on the thermal conversion of an industrial solid byproduct resulting from the pickling of metal surfaces, mainly containing iron (II) oxalate. In a fixed-bed reactor, the thermal conversion was investigated as a function of the operating temperature and overall time. The starting material and the products obtained after heat treatment were characterized in detail, using numerous qualitative and semi-quantitative techniques. The aim of this research was to determine the optimal operating conditions for the transformation of the industrial byproduct into a high-quality product. By varying the operating conditions, it was found that complete conversion of iron (II) oxalate to magnetite was achieved at high temperatures (i.e., 773 K and 873 K) after one hour of treatment. The resulting product had a low degree of crystallization, which increased slightly with an increasing reaction time at a temperature of 873 K, reaching a maximum of about 11%. The magnetite obtained can be used in the future as a starting material for chemical looping processes as a chemical/energy carrier for the production of hydrogen.

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.

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.

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.

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.

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.

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.

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.

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.