Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy.

Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome-MetS, and type 2 diabetes mellitus-DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and real-time quantitative polymerase chain reaction (RT-qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme-linked immunoassay (ELISA). DM2-CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Old and the New: Cardiovascular and Respiratory Alterations Induced by Acute JWH-018 Administration Compared to Δ9-THC-A Preclinical Study in Mice.

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus; EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018; 0.3-3-6 mg/kg) and Δ9-tetrahydrocannabinol (Δ9-THC; 0.3-3-6 mg/kg), administered in awake CD-1 male mice. The results showed that higher doses of JWH-018 (3-6 mg/kg) induced deep and long-lasting bradycardia, alternated with bradyarrhythmia, spaced out by sudden episodes of tachyarrhythmias (6 mg/kg), and characterized by ECG electrical parameters changes, sustained bradypnea, and systolic and transient diastolic hypertension. Otherwise, Δ9-THC provoked delayed bradycardia (minor intensity tachyarrhythmias episodes) and bradypnea, also causing a transient and mild hypertensive effect at the tested dose range. These effects were prevented by both treatment with selective CB1 (AM 251, 6 mg/kg) and CB2 (AM 630, 6 mg/kg) receptor antagonists and with the mixture of the antagonists AM 251 and AM 630, even if in a different manner. Cardio-respiratory and vascular symptoms could be induced by peripheral and central CB1 and CB2 receptors stimulation, which could lead to both sympathetic and parasympathetic systems activation. These findings may represent a starting point for necessary future studies aimed at exploring the proper antidotal therapy to be used in SCs-intoxicated patient management.

Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions?

JWH-018 is the most known compound among synthetic cannabinoids (SCs) used for their psychoactive effects. SCs-based products are responsible for several intoxications in humans. Cardiac toxicity is among the main side effects observed in emergency departments: SCs intake induces harmful effects such as hypertension, tachycardia, chest pain, arrhythmias, myocardial infarction, breathing impairment, and dyspnea. This study aims to investigate how cardio-respiratory and vascular JWH-018 (6 mg/kg) responses can be modulated by antidotes already in clinical use. The tested antidotes are amiodarone (5 mg/kg), atropine (5 mg/kg), nifedipine (1 mg/kg), and propranolol (2 mg/kg). The detection of heart rate, breath rate, arterial oxygen saturation (SpO2), and pulse distention are provided by a non-invasive apparatus (Mouse Ox Plus) in awake and freely moving CD-1 male mice. Tachyarrhythmia events are also evaluated. Results show that while all tested antidotes reduce tachycardia and tachyarrhythmic events and improve breathing functions, only atropine completely reverts the heart rate and pulse distension. These data may suggest that cardiorespiratory mechanisms of JWH-018-induced tachyarrhythmia involve sympathetic, cholinergic, and ion channel modulation. Current findings also provide valuable impetus to identify potential antidotal intervention to support physicians in the treatment of intoxicated patients in emergency clinical settings.

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.

Profiling the Acute Effects of Modified Risk Products: Evidence from the SUR-VAPES (Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking) Cluster Study.

PURPOSE OF REVIEW: Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP. RECENT FINDINGS: Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.

Impact of Tirofiban on Serum Troponin Changes in Patients Undergoing Carotid Artery Stenting: A Propensity Matched Analysis.

BACKGROUND: The optional periprocedural antithrombotic management for carotid artery stenting (CAS) is still debated. METHODS: We aimed to compare the procedural and 1-month outlook of patients undergoing CAS with tirofiban as parenteral antiplatelet therapy. We retrospectively compared patients receiving tirofiban during CAS versus those undergoing CAS without tirofiban, using propensity score matching. Ancillary antithrombotic therapy included in all patients aspirin, clopidogrel, and unfractioned heparin. The primary outcome was the change in serum troponin from baseline to postprocedural peak levels. A total of 30 patients undergoing CAS were included, 15 receiving tirofiban on top of heparin and dual oral antiplatelet therapy (DAPT) and 15 receiving only heparin and DAPT. Bail-out use of tirofiban was an exclusion criterion. RESULTS: Baseline troponin was 3.00 (0.06; 5.20) ng/mL in the tirofiban group vs. 4.6 (0.02; 13.10) ng/mL in the no-tirofiban group (P = 0.229), and postprocedural peak 3.5 (0.06; 5.50) ng/mL vs. 6.30 (0.09; 28.40) ng/mL (P = 0.191). Peak-baseline difference in troponin was lower in the tirofiban group than in the no-tirofiban group: 0.3 (0.00; 1.7) ng/mL vs. 1.3 (0.01; 10.00) ng/mL (P = 0.044); the relative peak-baseline change in troponin was analogously different: 24.3% (0%; 44.7%) vs. 50% (21.3%; 80.0%) (P = 0.039). No case of death, myocardial infarction, stroke, or transient ischemic attack occurred during in-hospital stay or at 1-month follow-up. CONCLUSIONS: Tirofiban during CAS might provide periprocedural myocardial protection and reduce myocardial injury as determined by serial troponin measurements.

Contact-force monitoring increases accuracy of right ventricular voltage mapping avoiding "false scar" detection in patients with no evidence of structural heart disease.

PURPOSE: Electroanatomical mapping (EAM) could increase cardiac magnetic resonance imaging (CMR) sensitivity in detecting ventricular scar. Possible bias may be scar over-estimation due to inadequate tissue contact. Aim of the study is to evaluate contact-force monitoring influence during EAM, in patients with idiopathic right ventricular arrhythmias. METHODS: 20 pts (13 M; 43 ± 12 y) with idiopathic right ventricular outflow tract (RVOT) arrhythmias and no structural abnormalities were submitted to Smarttouch catheter Carto3 EAM. Native maps included points collected without considering contact-force. EAM scar was defined as area ≥1 cm2 including at least 3 adjacent points with signal amplitude (bipolar <0.5 mV, unipolar 3,5 mV), surrounded by low-voltage border zone. EAM were re-evaluated offline, removing points collected with contact force <5 g. Finally, contact force-corrected maps were compared to the native ones. RESULTS: An EAM was created for each patient (345 ± 85 points). After removing poor contact points, a mean of 149 ± 60 points was collected. The percentage of false scar, collected during contact force blinded mapping compared to total volume, was 6.0 ± 5.2% for bipolar scar and 7.1 ± 5.9% for unipolar scar, respectively. No EAM scar was present after poor contact points removal. Right ventricular areas analysis revealed a greater number of points with contact force < 5 g acquired in free wall, where reduced mean bipolar and unipolar voltage were recorded. CONCLUSIONS: To date this is the first work conducted on structurally normal hearts in which contact-force significantly increases EAM accuracy, avoiding "false scar" related to non-adequate contact between catheter and tissue.

An overview of the molecular mechanisms underlying development and progression of bicuspid aortic valve disease.

Bicuspid aortic valve (BAV) is a common congenital heart malformation frequently associated with the development of aortic valve diseases and severe aortopathy, such as aortic dilatation, aneurysm and dissection. To date, different genetic loci have been identified in syndromic and non- syndromic forms of BAV. Among these, genes involved in the regulation of extracellular matrix remodelling, epithelial to mesenchymal transition and nitric oxide metabolism appear to be the main contributors to BAV pathogenesis. However, no- single gene model explains BAV inheritance, suggesting that more factors are simultaneously involved. In this regard, characteristic epigenetic and immunological profiles have been documented to contradistinguish BAV individuals. In this review, we provide a comprehensive overview addressing molecular mechanisms involved in BAV development and progression.

On the Road to Regeneration: "Tools" and "Routes" Towards Efficient Cardiac Cell Therapy for Ischemic Cardiomyopathy.

PURPOSE OF REVIEW: Cardiac regenerative medicine is a field bridging together biotechnology and surgical science. In this review, we present the explored surgical roads to cell delivery and the known effects of each delivery method on cell therapy efficiency. We also list the more recent clinical trials, exploring the safety and efficacy of delivery routes used for cardiac cell therapy approaches. RECENT FINDINGS: There is no consensus in defining which way is the most suitable for the delivery of the different therapeutic cell types to the damaged heart tissue. In addition, it emerged that the "delivery issue" has not been systematically addressed in each clinical trial and for each and every cell type capable of cardiac repair. Cardiac damage occurring after an ischemic insult triggers a cascade of cellular events, eventually leading to heart failure through fibrosis and maladaptive remodelling. None of the pharmacological or medical interventions approved so far can rescue or reverse this phenomenon, and cardiovascular diseases are still the leading cause of death in the western world. Therefore, for nearly 20 years, regenerative medicine approaches have focused on cell therapy as a promising road to pursue, with numerous preclinical and clinical testing of cell-based therapies being studied and developed. Nonetheless, consistent clinical results are still missing to reach consensus on the most effective strategy for ischemic cardiomyopathy, based on patient selection, diagnosis and stage of the disease, therapeutic cell type, and delivery route.

The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy.

PURPOSE OF REVIEW: Cell therapy for cardiovascular diseases is regarded as a rapidly growing field within regenerative medicine. Different cellular populations enriched for cardiac progenitor cells (CPCs), or derivate a-cellular products, are currently under preclinical and clinical evaluation. Here, we have reviewed the described mechanisms whereby resident post-natal CPCs, isolated in different ways, act as a therapeutic product on the damaged myocardium. RECENT FINDINGS: Several biological mechanisms of action have been described which can explain the multiple therapeutic effects of CPC treatment observed on cardiac function and remodelling. These mechanisms span from direct cardiovascular differentiation, through induction of resident progenitor proliferation, to paracrine effects on cardiac and non-cardiac cells mediated by exosomes and non-coding RNAs. All the reported mechanisms of action support an integrated view including cardiomyogenesis, cardioprotection, and anti-fibrotic effects. Moreover, future developments of CPC therapy approaches may support cell-free strategies, exploiting effective pleiotropic cell-derived products, such as exosomes.

The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine.

Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation.

The Positive Effects of Exercise in Chemotherapy-Related Cardiomyopathy.

Anthracyclines such as doxorubicin, daunorubicin, epirubicin, mitoxantrone and idarubicin, are powerful chemotherapeutic drugs used both in children and adult populations. Their properties made them particularly suitable for a large variety of neoplasms including breast adenocarcinoma, small cell lung cancer and acute leukemia. Early and late anthracycline-induced cardiotoxicity is a well-known phenomenon, and the incidence of heart failure in patients receiving doxorubicin is 2.2%, with a mortality rate over 60% at 2 years. Prognosis can be improved by prevention, early detection and treatment. A specific treatment for anthracycline-induced cardiotoxicity is not yet available, but non-pharmacological measures such as exercise, lifestyle changes and control of risk factors have shown a cardioprotective effect. Exercise training represents a viable non-pharmacological treatment as it increases cardiovascular reserve and endothelial function, regulates proapoptotic signaling, protects against reactive oxygen species (ROS), and decreases autophagy/lysosomal signaling. However, no current guidelines are available for prevention management in cancer patients. Pharmacological measures both for prevention and treatment are those used for heart failure (ß-blockers, angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, statins, dexrazoxane and aldosteron antagonists). In this chapter, we will discuss how the evaluation, monitoring and prevention of chemotherapy-related cardiomyopathy is correlated with physical exercise.

Current Insights and Novel Cardiovascular Magnetic Resonance-Based Techniques in the Prognosis of Non-Ischemic Dilated Cardiomyopathy.

Cardiac magnetic resonance (CMR) imaging has an important emerging role in the evaluation and management of patients with cardiomyopathies, especially in patients with dilated cardiomyopathy (DCM). It allows a non-invasive characterization of myocardial tissue, thus assisting early diagnosis and precise phenotyping of the different cardiomyopathies, which is an essential step for early and individualized treatment of patients. Using imaging techniques such as late gadolinium enhancement (LGE), standard and advanced quantification as well as quantitative mapping parameters, CMR-based tissue characterization is useful in the differential diagnosis of DCM and risk stratification. The purpose of this article is to review the utility of CMR in the diagnosis and management of idiopathic DCM, as well as risk prediction and prognosis based on standard and emerging CMR contrast and non-contrast techniques. This is consistent with current evidence and guidance moving beyond traditional prognostic markers such as ejection fraction.

Cardiovascular disease as part of Long COVID: A systematic review.

BACKGROUND: Long COVID syndrome has had a major impact on million patients' lives worldwide. The cardiovascular system is an important aspect of this multifaceted disease that may manifest in many ways. We have hereby performed a narrative review in order to identify the extent of the cardiovascular manifestations of the Long COVID syndrome. METHODS AND RESULTS: An in-depth systematic search of the literature has been conducted for this narrative review. The systematic search of PubMed and Cochrane databases yielded 3,993, of which 629 underwent full text screening. A total of 78 studies were included in the final qualitative synthesis and data evaluation. The pathophysiology of the cardiovascular sequelae of Long COVID syndrome and the cardiac manifestations and complications of Long COVID syndrome are critically evaluated. In addition, potential cardiovascular risk factors are assessed, and preventive methods and treatment options are examined in this review. CONCLUSIONS: This systematic review poignantly summarises the evidence from the available literature regarding the cardiovascular manifestations of Long COVID syndrome and reviews potential mechanistic pathways, diagnostic approaches, preventive measures and treatment options.

Electrocardiographic predictors of left ventricular scar in athletes with right bundle branch block premature ventricular beats.

AIMS: Right bundle branch block (RBBB) morphology non-sustained ventricular arrhythmias (VAs) have been associated with the presence of non-ischaemic left ventricular scar (NLVS) in athletes. The aim of this cross-sectional study was to identify clinical and electrocardiogram (ECG) predictors of the presence of NLVS in athletes with RBBB VAs. METHODS AND RESULTS: Sixty-four athletes [median age 39 (24-53) years, 79% males] with non-sustained RBBB VAs underwent cardiac magnetic resonance (CMR) with late gadolinium enhancement in order to exclude the presence of a concealed structural heart disease. Thirty-six athletes (56%) showed NLVS at CMR and were assigned to the NLVS positive group, whereas 28 athletes (44%) to the NLVS negative group. Family history of cardiomyopathy and seven different ECG variables were statistically more prevalent in the NLVS positive group. At univariate analysis, seven ECG variables (low QRS voltages in limb leads, negative T waves in inferior leads, negative T waves in limb leads I-aVL, negative T waves in precordial leads V4-V6, presence of left posterior fascicular block, presence of pathologic Q waves, and poor R-wave progression in right precordial leads) proved to be statistically associated with the finding of NLVS; these were grouped together in a score. A score ≥2 was proved to be the optimal cut-off point, identifying NLVS athletes in 92% of cases and showing the best accuracy (86% sensitivity and 100% specificity, respectively). However, a cut-off ≥1 correctly identified all patients with NLVS (absence of false negatives). CONCLUSION: In athletes with RBBB morphology non-sustained VAs, specific ECG abnormalities at 12-lead ECG can help in detecting subjects with NLVS at CMR.

In athletes with right bundle branch block (RBBB) morphology non-sustained ventricular arrhythmias (VAs), the presence of a non-ischaemic left ventricular scar (NLVS) may be highly suspected if one or more of the following electrocardiogram (ECG) characteristics are present at the 12-lead resting ECG: low QRS voltages in limb leads, negative T waves in inferior leads, negative T waves in limb leads I­aVL, negative T waves in precordial leads V4­V6, presence of left posterior fascicular block, presence of pathologic Q waves, and poor R-wave progression in right precordial leads. This score should be externally validated in a larger population of athletes with VAs. In athletes with RBBB morphology non-sustained Vas, attention should be placed on the 12-lead resting ECG to suspect the presence of an NLVS. In athletes with RBBB VAs and the presence of one or more of the identified ECG characteristics, a cardiac magnetic resonance with late gadolinium enhancement is useful to rule out an NLVS.

Unlocking the potential of artificial intelligence in sports cardiology: does it have a role in evaluating athlete's heart?

The integration of artificial intelligence (AI) technologies is evolving in different fields of cardiology and in particular in sports cardiology. Artificial intelligence offers significant opportunities to enhance risk assessment, diagnosis, treatment planning, and monitoring of athletes. This article explores the application of AI in various aspects of sports cardiology, including imaging techniques, genetic testing, and wearable devices. The use of machine learning and deep neural networks enables improved analysis and interpretation of complex datasets. However, ethical and legal dilemmas must be addressed, including informed consent, algorithmic fairness, data privacy, and intellectual property issues. The integration of AI technologies should complement the expertise of physicians, allowing for a balanced approach that optimizes patient care and outcomes. Ongoing research and collaborations are vital to harness the full potential of AI in sports cardiology and advance our management of cardiovascular health in athletes.

The role of echocardiography in sports cardiology: An expert opinion statement of the Italian Society of Sports Cardiology (SIC sport).

Transthoracic echocardiography (TTE) is routinely required during pre-participation screening in the presence of symptoms, family history of sudden cardiac death or cardiomyopathies <40-year-old, murmurs, abnormal ECG findings or in the follow-up of athletes with a history of cardiovascular disease (CVD). TTE is a cost-effective first-line imaging modality to evaluate the cardiac remodeling due to long-term, intense training, previously known as the athlete's heart, and to rule out the presence of conditions at risk of sudden cardiac death, including cardiomyopathies, coronary artery anomalies, congenital, aortic and heart valve diseases. Moreover, TTE is useful for distinguishing physiological cardiac adaptations during intense exercise from pathological behavior due to an underlying CVD. In this expert opinion statement endorsed by the Italian Society of Sports Cardiology, we discussed common clinical scenarios where a TTE is required and conditions falling in the grey zone between the athlete's heart and underlying cardiomyopathies or other CVD. In addition, we propose a minimum dataset that should be included in the report for the most common indications of TTE in sports cardiology clinical practice.