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Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups ( p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.

Telemedicine and remote monitoring devices, including implantable loop recorders (ILR), are increasingly adopted in the cardiologic setting. These are valuable tools in the arrhythmic stratification of patients at risk of sudden cardiac death, providing a tailored therapeutic management to prevent lethal arrhythmias. We report a case of an asymptomatic 18-year-old boy with a family history of syncope and cardiac arrest, who had a diagnosis of Brugada syndrome with an inducible type 1 pattern and carrier of a missense mutation of the SCN5A gene. In light of the risk factors, although not recommended by current guidelines, we decided to proceed with the implantation of an ILR with remote monitoring service. A few months later, an episode of asymptomatic sustained polymorphic ventricular tachycardia was promptly observed by the remote monitoring, leading to a timely implantation of a subcutaneous cardiac implantable defibrillator.

Cardiomyopathies (CMPs) are a group of myocardial disorders that are characterized by structural and functional abnormalities of the heart muscle. These abnormalities occur in the absence of coronary artery disease (CAD), hypertension, valvular disease, and congenital heart disease. CMPs are an increasingly important topic in the field of cardiovascular diseases due to the complexity of their diagnosis and management. In 2023, the ESC guidelines on cardiomyopathies were first published, marking significant progress in the field. The growth of techniques such as cardiac magnetic resonance imaging (CMR) and genetics has been fueled by the development of multimodal imaging approaches. For the diagnosis of CMPs, a multimodal imaging approach, including CMR, is recommended. CMR has become the standard for non-invasive analysis of cardiac morphology and myocardial function. This document provides an overview of the role of CMR in CMPs, with a focus on tissue mapping. CMR enables the characterization of myocardial tissues and the assessment of cardiac functions. CMR sequences and techniques, such as late gadolinium enhancement (LGE) and parametric mapping, provide detailed information on tissue composition, fibrosis, edema, and myocardial perfusion. These techniques offer valuable insights for early diagnosis, prognostic evaluation, and therapeutic guidance of CMPs. The use of quantitative CMR markers enables personalized treatment plans, improving overall patient outcomes. This review aims to serve as a guide for the use of these new tools in clinical practice.

Background: Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny., Methods and Results: High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD 14hi CD16 + ), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14 hi CD16 + ) characterized by H3K4me1 accumulation at NFkB-p65 promoter., Conclusions: Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition., (© 2024. The Author(s).)

Purpose of Review: Heart failure (HF) and erectile dysfunction (ED) are two common conditions that affect millions of men worldwide and impair their quality of life. ED is a frequent complication of HF, as well as a possible predictor of cardiovascular events and mortality. ED deserves more attention from clinicians and researchers., Recent Findings: The pathophysiology of ED in HF involves multiple factors, such as endothelial dysfunction, reduced cardiac output, neurohormonal activation, autonomic imbalance, oxidative stress, inflammation, and drug side effects. The diagnosis of ED in HF patients should be based on validated questionnaires or objective tests, as part of the routine cardiovascular risk assessment. The therapeutic management of ED in HF patients should be individualized and multidisciplinary, considering the patient's preferences, expectations, comorbidities, and potential drug interactions. The first-line pharmacological treatment for ED in HF patients with mild to moderate symptoms (NYHA class I-II) is phosphodiesterase type 5 inhibitors (PDE5Is), which improve both sexual function and cardiopulmonary parameters. PDE5Is are contraindicated in patients who use nitrates or nitric oxide donors for angina relief, and these patients should be advised to avoid sexual activity or to use alternative treatments for ED. Non-pharmacological treatments for ED, such as psychotherapy or couples therapy, should also be considered if there are significant psychosocial factors affecting the patient's sexual function or relationship. This review aims to summarize the most recent evidence regarding the prevalence of ED, the pathophysiology of this condition with an exhaustive analysis of factors involved in ED development in HF patients, a thorough discussion on diagnosis and management of ED in HF patients, providing practical recommendations for clinicians., (© 2023. The Author(s).)

Cangrelor, the first intravenous P2Y 12 inhibitor (P2Y 12 -I), has been approved on the basis of three large RCTs from the CHAMPION program which nevertheless have been criticized for the low bleeding risk of the enrolled patients, the large quote of chronic coronary syndromes, and the use of Clopidogrel as control arm even in the setting of acute coronary syndromes (ACS). We sought to investigate, in the setting of ACS, the comparative performance of Cangrelor in terms of in-hospital ischemic and haemorrhagic outcomes compared with the current gold-standard of oral P2Y 12 -I. The study retrospectively enrolled 686 consecutive patients admitted to the Divisions of Cardiology of Policlinico of Bari and L. Bonomo Hospital of Andria for ACS and treated with percutaneous coronary intervention. The study population was divided according to the P2Y 12 -I treatment strategy in two groups: patients given an oral P2Y 12 -I and patients receiving Cangrelor in the cath lab followed by an oral P2Y 12 -I. Clinical endpoints included death, ischemic and bleeding events occurring during hospital stay. Cangrelor treated patients presented higher clinical risk profile at presentation and faced higher death rate. However, after PS matching, in-hospital mortality resulted comparable between the groups and Cangrelor use was associated with reduced in-hospital definite stent thrombosis (p = 0.03). Data from our real-world registry highlight that, in the setting of ACS, Cangrelor is prevalently used in patients with very challenging clinical presentations. The adjusted analysis provides for the first time promising data on stent thrombosis reduction associated with Cangrelor use., (© 2023. The Author(s).)

Background: Impaired iron transport (IIT) is a form of iron deficiency (ID) defined as transferrin saturation (TSAT) < 20% irrespective of serum ferritin levels. It is frequently observed in heart failure (HF) where it negatively affects prognosis irrespective of anaemia., Objectives: In this retrospective study we searched for a surrogate biomarker of IIT., Methods: We tested the predictive power of red distribution width (RDW), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC) to detect IIT in 797 non-anaemic HF patients., Results: At ROC analysis, RDW provided the best AUC (0.6928). An RDW cut-off value of 14.2% identified patients with IIT, with positive and negative predictive values of 48 and 80%, respectively. Comparison between the true and false negative groups showed that estimated glomerular filtration rate (eGFR) was significantly higher ( p  = 0.0092) in the true negative vs. false negative group. Therefore, we divided the study population according to eGFR value: 109 patients with eGFR ≥ 90 ml/min/1.73 m 2 , 318 patients with eGFR 60-89 ml/min/1.73 m 2 , 308 patients with eGFR 30-59 ml/min/1.73 m 2 and 62 patients with eGFR < 30 ml/min/1.73 m 2 . In the first group, positive and negative predictive values were 48 and 81% respectively, 51 and 85% in the second group, 48 and 73% in the third group and 43 and 67% in the fourth group., Conclusion: RDW may be seen as a reliable marker to exclude IIT in non-anaemic HF patients with eGFR ≥60 ml/min/1.73 m 2 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MM declared a shared affiliation with the authors JC, AB, FDM, CV, BP, PA at the time of review., (© 2023 Campodonico, Carulli, Doni, Russo, Junod, Gaudenzi Asinelli, Bonomi, De Martino, Vignati, Pezzuto and Agostoni.)

Type 1 diabetes mellitus (T1DM) is a highly prevalent autoimmune disease causing the destruction of pancreatic islet β-cells. The resulting insulin production deficiency leads to a lifelong need for insulin re-placement therapy, systemic complications, and reduced life quality and expectancy. Cell therapy has been extensively attempted to restore insulin independence (IID), and autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) has appeared to give the most promising results, but with a highly variable quote of patients achieving IID across the studies. We performed a comprehensive review of the trials involving stem cells, and in particular AHST, for the treatment of T1DM. We then pooled the patients enrolled in the different trials and looked for the patient characteristics that could be associated with the achievement of IID. We found a significantly higher probability of achieving IID in older patients (OR 1.17, 95%CI 1.06-1.33, p = 0.002) and a significantly lower probability in patients with a history of ketoacidosis (OR 0.23, 95%CI 0.06-0.78, p = 0.023). This suggests that there could be a population of patients more likely to benefit from AHST, but further data would be required to depict the profile of the ideal candidate.

Endothelial progenitor cells (EPCs): The name embodies years of research and clinical expectations, but where are we now? Do these cells really represent the El Dorado of regenerative medicine? Here, past and recent literature about this eclectic, still unknown and therefore fascinating cell population will be discussed. This review will take the reader through a temporal journey that, from the first discovery, will pass through years of research devoted to attempts at their definition and understanding their biology in health and disease, ending with the most recent evidence about their pathobiological role in cardiovascular disease and their recent applications in regenerative medicine.

Background: Cardiac involvement significantly contributes to coronavirus disease 2019 (COVID-19) mortality.12-lead electrocardiogram (ECG) represents a fast, cheap, and easy to perform exam with the adjunctive advantage of the remote reporting possibility. In this study, we sought to investigate if electrocardiographic parameters can identify patients, deemed at low-risk at admission, who will face in-hospital unfavorable course., Methods: From March 1, 2020, through March 30, 2021, 384 consecutive patients with confirmed low-risk COVID-19 were hospitalized at the University Hospital of Bari (Italy). Criteria for low risk were: admission to the division of Pneumology or Infectious Diseases, no need for immediate (within 24 hours from admission) transfer to Intensive Care Unit or for respiratory support with invasive mechanical ventilation (IMV) or for circulation support (either mechanical or pharmacological). Admission ECGs were reviewed and interpreted by two expert cardiologists. The primary outcomes were in-hospital death and the composite outcome of in-hospital death and IMV., Results: In low-risk COVID-19 patients, atrial fibrillation (AF), poor R wave progression (PRWP), tachycardia, and right bundle branch block (RBBB) resulted as statistically significant and independent predictors of in-hospital all-cause mortality; AF, PRWP, Tachycardia, RBBB, and corrected QT interval showed to be statistically significant and independent risk factors for the occurrence of the composite endpoint of death and IMV., Conclusions: Our study demonstrated for the first time that RBBB and PRWP, assessed upon admission with ECG, are associated with unfavorable clinical course in a baseline low-risk population hospitalized for COVID-19.

Aims: Impaired iron transport (IIT) occurs frequently in heart failure (HF) patients, even in the absence of anaemia and it is associated with a poor quality of life and prognosis. The impact of IIT on exercise capacity, as assessed by the cardiopulmonary exercise test (CPET), in HF is at present unknown. The aim of this article is to evaluate in HF patients the impact on exercise performance of IIT, defined as transferrin saturation (TSAT) <20%., Methods and Results: We collected data of 676 patients hospitalized for HF. All underwent laboratory analysis, cardiac ultrasound, and CPET. Patients were grouped by the presence/absence of IIT and anaemia (haemoglobin <13 and <12 g/dL in male and female, respectively): Group 1 (G1) no anaemia, no IIT; Group 2 (G2) anaemia, no IIT; Group 3 (G3) no anaemia, IIT; Group 4 (G4) anaemia and IIT. Peak oxygen uptake (peakVO2) reduced from G1 to G3 and from G2 to G4 (G1: 1266 ± 497 mL/min, G2: 1011 ± 385 mL/min, G3: 1041 ± 395 mL/min, G4: 833 ± 241 mL/min), whereas the ventilation to carbon dioxide relationship slope (VE/VCO2 slope) increased (G1: 31.8 ± 7.5, G2: 34.5 ± 7.4, G3: 36.1 ± 10.2, G4: 37.5 ± 8.4). At multivariate regression analysis, peakVO2 independent predictors were anaemia, brain natriuretic peptide (BNP), and left ventricular ejection fraction, whereas VE/VCO2 slope independent predictors were IIT and BNP., Conclusion: In HF IIT is associated with exercise performance impairment independently from anaemia, and it is a predictor of elevated VE/VCO2 slope, a pivotal index of HF prognosis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Dual antiplatelet therapy (DAPT) with acetylsalicylic acid and oral P2Y12 inhibitor (P2Y12-I) represents the standard of care for patients with acute coronary syndromes (ACS) or with chronic coronary syndromes (CCS) treated with percutaneous coronary intervention (PCI). Cangrelor, the first intravenous P2Y12-I, is deemed to overcome the drawbacks of the oral administration; nevertheless, real world data on this new drug are scanty. We sought to investigate routine clinical use of cangrelor in four interventional centers of Italy., Methods: We enrolled 241 consecutive patients (196 ACS, 45 CCS) treated with cangrelor during PCI. Drug administration modalities and in-hospital clinical outcomes were evaluated. A subanalysis in patients selected based on the CHAMPION Phoenix trial inclusion/exclusion criteria (CHAMPION-like subpopulation) was also performed., Results: Cangrelor was mainly utilized in ACS patients, who presented poorer clinical conditions and higher bleeding risk. Cangrelor was given only in P2Y12-I naïve patients; switch to clopidogrel was always done at the end of the infusion, while ticagrelor or prasugrel were prevalently given 30 minutes before. In-hospital mortality was 10.0% and GUSTO moderate/severe bleeding was 2.5%. Bleeding data showed nevertheless to be in line with the CHAMPION Phoenix results in the "CHAMPION-like" subpopulation., Conclusions: Cangrelor was predominantly used in ACS with modalities substantially in accord with the label indications. Poor clinical outcomes are due to the prevalent utilization in highly challenging clinical settings, nevertheless the rate of bleeding and stent thrombosis are in line with the randomized trials if analyzed in a subpopulation of comparable risk profile.

Background and Aims: Despite the relation between autoimmune diseases and increased atherosclerotic risk is established, the influence of autoimmune disorders on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is only partly known. ISR is an aberrant reparative process mainly characterized by an increased number of vascular smooth muscle cells and excessive deposition of extracellular proteoglycans and type III collagen. Chronic inflammation, always present in autoimmune diseases, modulates the endothelial response to PCI. Aim of this review is to resume the current evidence on the association between ISR and autoimmune diseases, focusing on pathogenic mechanisms and therapeutic targets., Methods: We conducted a comprehensive review of the literature on the relationship between ISR and insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid-antibodies syndrome (APS), inflammatory bowel diseases (IBD), and Hashimoto's thyroiditis (HT)., Results: Patients affected with IDDM, RA, SLE, APS, IBD and HT proved to face higher rates of ISR compared to the general population. The endothelial dysfunction seems the principal common pathogenic pathway for ISR and is attributed to both the immune system disorder and the systemic inflammation. Some evidence suggested that methotrexate and anti-tumor necrosis factor treatments can be effective in reducing ISR, while antibodies against vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 showed to reduce neointimal hyperplasia in animal models., Conclusions: Autoimmune diseases are a risk factor for ISR. The study of the potential cardiovascular benefits of the current therapies, mainly anti-inflammatory drugs, and the pursuit of innovative treatments appear of paramount interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2019. Published by Elsevier Inc.)

We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The following protocol was used in the management of 25 hospitalised patients with acute cerebrovascular episodes: 4 vials Hydergine per day (slow venous drip) during the entire stay in hospital, with glycerol, diuretics, papaverine, cituridine, etc., during the initial period. Good results were noted in 18 cases (72%), including complete or nearly complete recovery of mobility and marked improvement of the entire clinical picture. A modest result was obtained in 4 cases and a fair result in one. Two subjects died, one from cardiographic shock and the other from supravening deep coma. It is considered that the protocol described is definitely useful in the medical treatment of cerebral ictus.