Intermittent ventricular pre-excitation in symptomatic adults: Always a marker of low risk?

BACKGROUND: Intermittent ventricular pre-excitation was considered a low-risk marker for sudden death. However, to date, some studies do not exclude the existence of accessory pathways (APs) with high-risk intermittent antegrade conductive properties. According to current European Guidelines, high-risk features of APs are antegrade pathway conduction ≤250 ms in baseline or during the adrenergic stimulus, inducibility of atrioventricular reciprocating tachycardias (AVRT), inducibility of pre-excited atrial fibrillation (AF), and presence of multiple APs. For all of these transcatheter ablation is recommended. The aim of our study was to evaluate the existence of differences in risk characteristics between patients with intermittent pre-excitation (IPX) and those with persistent pre-excitation (PPX), from a sample of adults with ventricular pre-excitation and symptoms like palpitations. METHODS: 293 adults [IPX: 51 (17.4%); PPX: 242 (82.6%)] underwent electrophysiological study and then catheter ablation of their APs if arrhythmia inducibility (AVRT/AF) was noted, or, conversely, if it was appreciated a fast AP antegrade conduction, in baseline or during intravenous isoproterenol infusion, or if multiple APs were detected. RESULTS: There were no statistically significant differences in demographic characteristics (age and gender), AVRT/AF inducibility, antegrade conductive properties, the prevalence of multiple APs, and APs locations between IPX and PPX patients. CONCLUSIONS: In our study, patients with IPX did not show significant differences in clinical and electrophysiological features versus PPX patients.

Computed tomography-derived left atrial volume index, sex, and age to predict the presence and the extent of left atrial low-voltage zones in patients with atrial fibrillation: The ZAQ score.

BACKGROUND: Pulmonary vein isolation is the cornerstone of catheter ablation in patients with atrial fibrillation (AF). However, with advanced left atrial (LA) structural changes, additional targeted catheter ablation of low-voltage zones (LVZs) has produced favorable results. Therefore, with the advent of single-shot techniques, it would be helpful to predict the presence of LVZs before an ablation procedure. OBJECTIVE: We hypothesized that computed tomography (CT)-derived left atrial volume index (LAVI), in combination with other objective parameters, could be used to develop a score able to predict the presence of LVZs. METHODS: In a large cohort of patients undergoing their first AF ablations, comprehensive echocardiographic evaluations and cardiac CT were performed. During the electrophysiological studies, LA geometry and electroanatomic voltage maps were created. LVZs were defined as areas ≥1 cm2 with bipolar peak-to-peak voltage amplitudes ≤0.5 mV. RESULTS: In a derivation cohort of 374 patients, predictors of LVZs were identified by regression analysis and used to build the Zentralklinik Bad Berka and University of L'Aquila (ZAQ) score (age ≥65 years; female sex; and CT-LAVI ≥57 mL/m2 ). The ZAQ score of 2 points accurately identified the presence and the extent of LVZs (area under the curve [AUC], 0.809; 95% confidence interval [CI], 0.758-0.861; P < .001 and 3 [interquartile range, IQR, 1.5-4.5] vs 7 cm2 [IQR 4-9]; P = .001). In a validation cohort of 103 patients, the predictive value of the score was confirmed (AUC, 0.793; 95% CI, 0.709-0.878; P < .001 and 4 [IQR, 2-7] vs 11.5 cm2 [IQR, 8-16.5]; P = .001). CONCLUSIONS: The ZAQ score identifies LVZs and may be useful for planning the ablation strategy ahead of time.

Analysis of Risk Factors Independently Associated with Cognitive Impairment in Patients with Permanent Atrial Fibrillation: A Cross-sectional Observational Study.

BACKGROUND AND OBJECTIVE: Atrial Fibrillation (AF) is associated with an increased risk of stroke and development of cognitive impairment. Our cross-sectional study aims to identify risk factors for cognitive impairment in patients with permanent AF. MATERIALS AND METHODS: 212 consecutive outpatients with history of permanent AF lasting more than 1 year were enrolled and the Short Portable Mental Status Questionnaire (SPMSQ) was used to assess cognitive impairment (number of errors ≥5). The type of antithrombotic therapy, the time in therapeutic range (TTR) in case of treatment with warfarin and the degree of heart rate (HR) control (upon Holter ECG monitoring) were also assessed. RESULTS: ROC curve analysis indicated that TTR was associated with cognitive impairment (AUC 0.85 ± 0.03; 95% CI 0.77-0.88; p < 0.0001). Multivariate logistic regression analysis showed an independent association of previous cerebrovascular or cardiovascular events (OR 7.24, 95% CI 1.37-38.25; p = 0.020), aspirin therapy instead of anticoagulant therapy (OR 24.74, 95% CI 1.27-482.12; p = 0.034), warfarin use with TTR ≤60% (OR 21.71 , 95%CI 4.35-108; p < 0.001) and an average daily HR either <60 bpm or >100 bpm (OR 6.04, 95% 1.09-33.29; p = 0.039) with cognitive impairment. CONCLUSION: Among patients with permanent AF, cognitive impairment is more frequent in those with inadequate antithrombotic therapy (aspirin therapy instead of anticoagulant therapy) and with suboptimal oral anticoagulation (TTR ≤60%) or heart rate control. Efforts should be made to optimize therapies related to these parameters.

Association between Corrected QT Interval and C-Reactive Protein in Patients with Inflammatory Bowel Diseases.

Background and objectives: Electrocardiograph abnormalities (i.e., QT interval prolongation) have been described in inflammatory bowel diseases (IBD). We aimed to measure the QT interval in a cohort of patients with IBD and to analyze its relationship with clinical and inflammatory activity. Materials and Methods: We performed a cross-sectional study that included 38 IBD outpatients and 38 "age- and sex-matched" healthy controls. Nine patients had active IBD, and 29 were in clinical remission. Among the latter, 10 patients had sustained (lasting >1 year) and 19 had short-term remission (≤1 year). Corrected QT (QTc) interval was measured on standard 12-lead electrocardiograph. A systematic review of the literature on studies investigating the QT interval in patients with IBD was also performed. Results: QTc interval values were similar between IBD patients and healthy controls (417.58 ± 22.05 ms vs. 409.13 ± 19.61 ms, respectively; p: 0.479). Patients with active IBD had significantly higher QTc values (435.11 ± 27.31 ms) than both controls (409.13 ± 19.61 ms) and patients in remission (412.14 ± 17.33 ms) (p: 0.031). Post hoc analysis showed that the difference in QTc values between active IBD and remission was attributable to the group of patients with sustained remission (p < 0.05). Lastly, a significant correlation between QTc interval and C-reactive protein (CRP) values was observed (Spearman test: r = 0.563; p: 0.0005). Conclusions: Our study demonstrates an association between QTc duration and both clinical and inflammatory activity in patients with IBD. The higher the CRP value, the longer is the QTc duration. For practical purposes, all patients with active IBD should undergo a standard ECG. Prescription of drugs able to modify the QT interval should be avoided in patients with active IBD. The systematic review of the literature indicated that this is the first published study demonstrating an association between the QTc duration and CRP values in patients with IBD.

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.

Cardiovascular and Metabolic Comorbidities in Rheumatoid Arthritis.

PURPOSE OF THE REVIEW: An increased prevalence of cardiovascular risk factors in rheumatoid arthritis (RA) is reported. The absolute cardiovascular risk in RA patients is higher than in the general population, and although the RA prognosis has gradually improved, premature cardiovascular (CV) mortality remains a matter of fact. The purpose of this review is to shed light on CV and metabolic involvement in RA, with the aim of defining its best management. RECENT FINDINGS: Multiple lines of evidence have revealed common mechanisms behind inflammatory and CV diseases and clarified the metabolic and CV pathways involved in RA and the effects of different pharmacological treatments. CV risk assessment should be mandatory in all RA patients, taking into account the impact of both diseases on patient's prognosis. Therefore, a multidisciplinary approach is the best management, and rheumatologists, cardiologists, and general practitioners must work together to significantly improve outcome and quality of life in RA patients. Future research could investigate the potential beneficial effects of a more aggressive pharmacological treatment of CV and metabolic risk factors.

Determinants of operator radiation exposure during percutaneous coronary procedures.

BACKGROUND: Radiation exposure is an important issue for interventional cardiologists that is often underevaluated. Our aim was to evaluate determinants of operator radiation exposure during percutaneous coronary procedures. METHODS: The RADIANT (NCT01974453) is a prospective, single-center observational study involving 4 expert operators and 2 fellows performing percutaneous coronary procedures. The operator radiation dose was evaluated using dedicated electronic dosimeters in 2,028 procedures: 1,897 transradial access (TRA; 1,120 right and 777 left TRA) and 131 transfemoral access (TFA). RESULTS: In the whole population, operator radiation dose at the thorax did not differ between TFA (9µSv [interquartile range 5-18µSv]) and TRA (9µSv [4-21µSv]), but after propensity score matching analysis, TFA showed lower dose (9µSv [5-18µSv]) compared with TRA (17µSv [9-28µSv], P<.001). In the whole transradial group, left TRA (5µSv [2-12µSv]) was associated with significant lower operator dose compared with right TRA (13µSv [6-26µSv], P<.001).The use of adjunctive protective pelvic drapes was significantly associated with lower radiation doses compared with procedures performed without drapes (P<.001). Among the operators, an inverse relation between height and dose was observed. Finally, left projections and the use of angiographic systems not dedicated for coronary and high frame rates were all associated with a significant higher operator radiation exposure. CONCLUSIONS: In a high-volume center for transradial procedures, TFA is associated with lower operator radiation dose compared with TRA. The use of adjunctive anti-rx drapes seems a valuable tool to reduce the higher operator radiation exposure associated with TRA.

Radial artery occlusion and hand strength after percutaneous coronary procedures: Results of the HANGAR study.

OBJECTIVES: The aim of this prospective study was to evaluate muscle force of the hand, thumb, and forefinger in patients with prolonged radial occlusion after transradial percutaneous coronary procedures. BACKGROUND: There are no data on hand strength and function in patients with prolonged radial occlusion after percutaneous coronary procedures. METHODS: Elective patients with chronic stable angina undergoing percutaneous coronary procedures were evaluated the day before the procedure for radial artery patency, Allen test, hand grip, and thumb and forefinger pinch tests. The same measures were performed the day after the procedure and at follow-up. At follow-up, patients were divided in two groups according to the radial patency (group 1) or occlusion (group 2). RESULTS: Of the 99 patients included in the study, 90 patients had a patent radial artery (group 1), and nine (9.1%) patients had an occluded artery (group 2). At baseline, there were no significant differences in hand grip test between the two groups (42 ± 11 kg in group 1 and 41 ± 17 kg in group 2, P = 0.74). In both groups, after the procedure, the hand grip test values was significantly reduced compared with baseline values (40 ± 11 kg in group 1, P < 0.0001 and 37 ± 17 kg in group 2, P = 0.007). Finally, at follow-up, in both groups, the hand grip test values returned to baseline values. Thumb and forefinger pinch tests did not show significant differences after the procedure and at follow-up, compared with baseline. CONCLUSIONS: Radial artery occlusion after percutaneous coronary procedures was not associated with a reduction in hand and finger strength.

Dose-dense nonpegylated liposomal Doxorubicin and docetaxel combination in breast cancer: dose-finding study.

BACKGROUND: Anthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose-finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC-D99) and docetaxel (DTX) as a dose-dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac. METHODS: Twenty-four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra- and interpatient approach was planned in two sequential steps. In the first step, TLC-D99 was administered at dose levels of 40, 45, and 50 mg/m(2) plus DTX at a fixed dose of 50 mg/m(2). In the second step, TLC-D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m(2). Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony-stimulating factor was scheduled on day 2. Dose-limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was <50% or ≥50%, respectively; severe arrhythmia; and symptomatic heart failure. LVEF was evaluated by echocardiography every two cycles, and precursor brain natriuretic peptide (pBNP) and cardiac troponin I (cTnI) were monitored on days 1 and 2. RESULTS: Five DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC-D99 50 mg/m(2) and DTX 65 mg/m(2). Cumulatively, mild (G1-G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1-G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%. CONCLUSION: Dose-dense TLC-D99 50 mg/m(2) and DTX 65 mg/m(2) can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m(2) per week, respectively.

TGFß-specific T cells induced by a TGFß-derived immune modulatory vaccine both directly and indirectly modulate the phenotype of tumor-associated macrophages and fibroblasts.

The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive. We recently developed a transforming growth factor (TGF)ß-based immune modulatory vaccine that controlled tumor growth in a murine model of pancreatic cancer by targeting immunosuppression and desmoplasia in the TME. We found that treatment with the TGFß vaccine not only reduced the percentage of M2-like tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor but polarized CAFs away from the myofibroblast-like phenotype. However, whether the immune modulatory properties of the TGFß vaccine on TAM and CAF phenotypes are a direct consequence of the recognition and subsequent targeting of these subsets by TGFß-specific T cells or an indirect consequence of the overall modulation induced within the TME remains unknown. Recognition of M2 macrophages and fibroblast by TGFß-specific T cells was assessed by ELISpot and flow cytometry. The indirect and direct effects of the TGFß vaccine on these cell subsets were evaluated by culturing M2 macrophages or fibroblasts with tumor-conditioned media or with T cells isolated from the spleen of mice treated with the TGFß vaccine or a control vaccine, respectively. Changes in phenotype were assessed by flow cytometry and Bio-Plex multiplex system (Luminex). We found that TGFß-specific T cells induced by the TGFß vaccine can recognize M2 macrophages and fibroblasts. Furthermore, we demonstrated that the phenotype of M2 macrophages and CAFs can be directly modulated by TGFß-specific T cells induced by the TGFß vaccine, as well as indirectly modulated as a result of the immune-modulatory effects of the vaccine within the TME. TAMs tend to have tumor-promoting functions, harbor an immunosuppressive phenotype and are linked to decreased overall survival in pancreatic cancer when they harbor an M2-like phenotype. In addition, myofibroblast-like CAFs create a stiff extracellular matrix that restricts T cell infiltration, impeding the effectiveness of immune therapies in desmoplastic tumors, such as pancreatic ductal adenocarcinoma. Reducing immunosuppression and immune exclusion in pancreatic tumors by targeting TAMs and CAFs with the TGFß-based immune modulatory vaccine emerges as an innovative strategy for the generation of a more favorable environment for immune-based therapies, such as immune checkpoint inhibitors.

Impact of COVID-19 on the cardiovascular health of women: a review by the Italian Society of Cardiology Working Group on 'gender cardiovascular diseases'.

The coronavirus disease 19 (COVID-19), due to coronavirus 2 (SARS-CoV-2) infection, presents with an extremely heterogeneous spectrum of symptoms and signs. COVID-19 susceptibility and mortality show a significant sex imbalance, with men being more prone to infection and showing a higher rate of hospitalization and mortality than women. In particular, cardiovascular diseases (preexistent or arising upon infection) play a central role in COVID-19 outcomes, differently in men and women. This review will discuss the potential mechanisms accounting for sex/gender influence in vulnerability to COVID-19. Such variability can be ascribed to both sex-related biological factors and sex-related behavioural traits. Sex differences in cardiovascular disease and COVID-19 involve the endothelial dysfunction, the innate immune system and the renin-angiotensin system (RAS). Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19 and it shows hormone-dependent actions. The incidence of myocardial injury during COVID-19 is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders among men. Its pathogenesis is not fully elucidated, but the main theories foresee a direct role for the ACE2 receptor, the hyperimmune response and the RAS imbalance, which may also lead to isolated presentation of COVID-19-mediated myopericarditis. Moreover, the latest evidence on cardiovascular diseases and their relationship with COVID-19 during pregnancy will be discussed. Finally, authors will analyse the prevalence of the long-covid syndrome between the two sexes and its impact on the quality of life and cardiovascular health.

Tailoring the Ablative Strategy for Atrial Fibrillation: A State-of-the-Art Review.

In spite of technological progress and the improving skills of operators, atrial fibrillation (AF) ablation results appear to date to be at a plateau. In any case, the superiority of ablation over pharmacological therapy in terms of effectiveness, reduction of hospitalizations, and improvement has been well demonstrated in recent randomized trials. Triggers, substrate, and modulating factors (elements of Coumel's triangle) play different roles in paroxysmal and persistent AF, so induction and perpetuation mechanisms of arrhythmia may be different in each patient. Although effective ablative strategies are available for the treatment of paroxysmal AF triggers and persistent AF substrates, an adequate clinical evaluation of the patient is crucial in order to increase the chances of success. Recognizing triggers allows not only performing an effective ablation but also to avoid unnecessary lesions and at the same time reducing the risk of complications. AF beginning and triggers could be recorded by 12-lead ECG, continuous Holter monitoring, or implantable devices. In case of an unsuccessful noninvasive evaluation, nonpulmonary vein triggers should be investigated with an electrophysiological study. Persistent AF needs more effort to perform an accurate substrate characterization. Among the many methods proposed, recently the use of high-density mapping and multipolar catheters seems of particular benefit in order to clarify the arrhythmia mechanisms. Surgical and hybrid techniques allow to treat regions such as the posterior wall or Bachmann's bundle, which is fundamental for an ablative strategy that goes beyond just pulmonary vein isolation. Too often, patients are referred to electrophysiology laboratories without adequate preprocedural screening and planning in order to submit them to a standard "ready-made" procedure. The accurate search for triggers in paroxysmal AF and the correct recognition of the link between a possible underlying heart disease and the substrate in persistent AF could allow us to tailor the interventional approach in order to overcome the current plateau, increasing ablative procedure success and minimizing complications.

Sport Related Sudden Death: The Importance of Primary and Secondary Prevention.

Sports are a double-edged sword. On the one hand, cardiovascular benefits from sports activity are well-known, and on the other hand, sports may increase the risk of sudden cardiac death (SCD) in subjects with known or unknown cardiovascular diseases. SCD is rare but has a very strong emotional issue. There are many examples involving famous professional athletes, but this is only scratching the surface of a widespread phenomenon that also involves amateur athletes. The importance of safely performing physical activity appears clear in both professional and amateur athletes. In particular, the former undergo a pre-participation screening for SCD primary prevention with different recommendations in each country. On the other hand, a medical examination is not mandatory for non-professional athletes and, therefore, for people who practice sports as an amateur. Widespread distribution of automatic external defibrillators and people trained for cardiopulmonary resuscitation are necessary to promote secondary prevention of SCD. We briefly report a case series of athletes with aborted SCD during sports activity in order to underline and discuss in this review the previously highlighted issues.

Managing athletes with palpitations of unknown origin with an external loop recorder: a cohort study.

BACKGROUND: Palpitations in athletes are usually benign, but the presence of major cardiac arrhythmias should be ruled out despite the infrequent appraisal of symptoms. External loop recorders (ELR) are promising to identify arrhythmias in these circumstances, but experiences in athletes are lacking. We aimed to investigate the feasibility and diagnostic yield of an ELR in athletes with unexplained palpitations in a cohort study. METHODS: One hundred twenty-two consecutive subjects (61 athletes and 61 sedentary controls) with sporadic palpitations and inconclusive diagnosis were enrolled and equipped with an ELR. Findings were categorized as major and minor arrhythmic findings, non-arrhythmic findings or negative monitoring. RESULTS: Long-term ELR monitoring was feasible in all subjects, with median duration of 12 (11; 15) days. Major arrhythmic events during palpitations were found in 9 (14.8%) athletes: 7 experienced sustained paroxysmal supraventricular tachycardia, and 2 had non sustained ventricular tachycardia. Minor arrhythmic events (premature supraventricular or ventricular beats) were observed in 13 athletes (21.3%). Non-arrhythmic findings (i.e., sinus rhythm or sinus tachycardia) were recorded in 28 athletes (45.9%), whereas 11 (18%) had negative monitoring. In the sedentary group, arrhythmic events were similar for types and frequency to athletes. The diagnostic yield of loop monitoring was 82.8% in the overall population and 82.0% in the athlete's group. CONCLUSIONS: In the management of an athlete symptomatic with unexplained palpitations after 24-hour ECG monitoring and stress test, ELR is an efficient tool to identify major arrhythmic events, which can be present in up to 10% of symptomatic athletes during practice and competition.

CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment.

CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis. CCL22 was shown to play a key role in suppressing anti-cancer immune responses in different cancer types. Recently, we showed that CCL22-specific T cells generated from cancer patients could kill CCL22-expressing tumor cells and directly influence the levels of CCL22 in vitro. The present study aimed to provide a rationale for developing a CCL22-targeting immunotherapy. Vaccination with CCL22-derived peptides induced CCL22-specific T-cell responses in both BALB/c and C57BL/6 mice, assessed by interferon-γ secretion ex vivo. Anti-tumor efficacy of the peptides was evaluated in mouse models engrafted with syngeneic tumor models showing a reduced tumor growth and prolonged survival of the treated mice. Vaccination induced changes in the cellular composition of immune cells that infiltrated the tumor microenvironment assessed with multicolor flow cytometry. In particular, the infiltration of CD8+ cells and M1 macrophages increased, which increased the CD8/Treg and the M1/M2 macrophage ratio. This study provided preclinical evidence that targeting CCL22 with CCL22 peptide vaccines modulated the immune milieu in the tumor microenvironment. This modulation led to an augmentation of anti-tumor responses. This study provided a rationale for developing a novel immunotherapeutic modality in cancer.

TGFß-derived immune modulatory vaccine: targeting the immunosuppressive and fibrotic tumor microenvironment in a murine model of pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with very poor survival, making it the third and fourth leading cause of all cancer-related deaths in the USA and European Union, respectively. The tumor microenvironment (TME) in PDAC is highly immunosuppressive and desmoplastic, which could explain the limited therapeutic effect of immunotherapy in PDAC. One of the key molecules that contributes to immunosuppression and fibrosis is transforming growth factor-ß (TGFß). The aim of this study was to target the immunosuppressive and fibrotic TME in PDAC using a novel immune modulatory vaccine with TGFß-derived peptides in a murine model of pancreatic cancer. METHODS: C57BL/6 mice were subcutaneously inoculated with Pan02 PDAC cells. Mice were treated with TGFß1-derived peptides (major histocompatibility complex (MHC)-I and MHC-II-restricted) adjuvanted with Montanide ISA 51VG. The presence of treatment-induced TGFß-specific T cells was assessed by ELISpot (enzyme-linked immunospot). Changes in the immune infiltration and gene expression profile in tumor samples were characterized by flow cytometry, reverse transcription-quantitative PCR (RT-qPCR), and bulk RNA sequencing. RESULTS: Treatment with immunogenic TGFß-derived peptides was safe and controlled tumor growth in Pan02 tumor-bearing mice. Enlargement of tumor-draining lymph nodes in vaccinated mice positively correlated to the control of tumor growth. Analysis of immune infiltration and gene expression in Pan02 tumors revealed that TGFß-derived peptide vaccine increased the infiltration of CD8+ T cells and the intratumoral M1/M2 macrophage ratio, it increased the expression of genes involved in immune activation and immune response to tumors, and it reduced the expression of myofibroblast-like cancer-associated fibroblast (CAF)-related genes and genes encoding fibroblast-derived collagens. Finally, we confirmed that TGFß-derived peptide vaccine actively modulated the TME, as the ability of T cells to proliferate was restored when exposed to tumor-conditioned media from vaccinated mice compared with media from untreated mice. CONCLUSION: This study demonstrates the antitumor activity of TGFß-derived multipeptide vaccination in a murine tumor model of PDAC. The data suggest that the vaccine targets immunosuppression and fibrosis in the TME by polarizing the cellular composition towards a more pro-inflammatory phenotype. Our findings support the feasibility and potential of TGFß-derived peptide vaccination as a novel immunotherapeutic approach to target immunosuppression in the TME.

Arginase-2-specific cytotoxic T cells specifically recognize functional regulatory T cells.

BACKGROUND: High expression of the metabolic enzyme arginase-2 (ARG2) by cancer cells, regulatory immune cells, or cells of the tumor stroma can reduce the availability of arginine (L-Arg) in the tumor microenvironment (TME). Depletion of L-Arg has detrimental consequences for T cells and leads to T-cell dysfunction and suppression of anticancer immune responses. Previous work from our group has demonstrated the presence of proinflammatory ARG2-specific CD4 T cells that inhibited tumor growth in murine models on activation with ARG2-derived peptides. In this study, we investigated the natural occurrence of ARG2-specific CD8 T cells in both healthy donors (HDs) and patients with cancer, along with their immunomodulatory capabilities in the context of the TME. MATERIALS AND METHODS: A library of 15 major histocompatibility complex (MHC) class I-restricted ARG2-derived peptides were screened in HD peripheral blood mononuclear cells using interferon gamma (IFN-γ) ELISPOT. ARG2-specific CD8 T-cell responses were identified using intracellular cytokine staining and ARG2-specific CD8 T-cell cultures were established by enrichment and rapid expansion following in vitro peptide stimulation. The reactivity of the cultures toward ARG2-expressing cells, including cancer cell lines and activated regulatory T cells (Tregs), was assessed using IFN-γ ELISPOT and a chromium release assay. The Treg signature was validated based on proliferation suppression assays, flow cytometry and quantitative reverse transcription PCR (RT-qPCR). In addition, vaccinations with ARG2-derived epitopes were performed in the murine Pan02 tumor model, and induction of ARG2-specific T-cell responses was evaluated with IFN-γ ELISPOT. RNAseq and subsequent GO-term and ImmuCC analysis was performed on the tumor tissue. RESULTS: We describe the existence of ARG2-specific CD8+ T cells and demonstrate these CD8+ T-cell responses in both HDs and patients with cancer. ARG2-specific T cells recognize and react to an ARG2-derived peptide presented in the context of HLA-B8 and exert their cytotoxic function against cancer cells with endogenous ARG2 expression. We demonstrate that ARG2-specific T cells can specifically recognize and react to activated Tregs with high ARG2 expression. Finally, we observe tumor growth suppression and antitumorigenic immunomodulation following ARG2 vaccination in an in vivo setting. CONCLUSION: These findings highlight the ability of ARG2-specific T cells to modulate the immunosuppressive TME and suggest that ARG2-based immunomodulatory vaccines may be an interesting option for cancer immunotherapy.

Peptide vaccination activating Galectin-3-specific T cells offers a novel means to target Galectin-3-expressing cells in the tumor microenvironment.

Galectin-3 (Gal3) can be expressed by many cells in the tumor microenvironment (TME), including cancer cells, cancer-associated fibroblasts, tumor-associated macrophages, and regulatory T cells (Tregs). In addition to immunosuppression, Gal3 expression has been connected to malignant cell transformation, tumor progression, and metastasis. In the present study, we found spontaneous T-cell responses against Gal3-derived peptides in PBMCs from both healthy donors and cancer patients. We isolated and expanded these Gal3-specific T cells in vitro and showed that they could directly recognize target cells that expressed Gal3. Finally, therapeutic vaccination with a long Gal3-derived peptide epitope, which induced the expansion of Gal3-specific CD8+ T cells in vivo, showed a significant tumor-growth delay in mice inoculated with EO771.LMB metastatic mammary tumor cells. This was associated with a significantly lower percentage of both Tregs and tumor-infiltrating Gal3+ cells in the non-myeloid CD45+CD11b- compartment and with an alteration of the T-cell memory populations in the spleens of Gal3-vaccinated mice. These results suggest that by activating Gal3-specific T cells by an immune-modulatory vaccination, we can target Gal3-producing cells in the TME, and thereby induce a more immune permissive TME. This indicates that Gal3 could be a novel target for therapeutic cancer vaccines.

The PREHAMI (PREsillion™ in high-risk acute myocardial infarction) registry: in-hospital and long-term outcomes.

OBJECTIVES: To evaluate the efficacy of the new Cobalt-Chromium (Co-Cr) Presillion™ stent for the treatment of high-risk acute myocardial infarction (MI) patients. BACKGROUND: Percutaneous coronary intervention (PCI) with stent represents the gold standard treatment for acute MI. METHODS AND RESULTS: We enrolled patients with high-risk acute MI (either ST-segment elevation MI or non-ST-segment elevation MI) treated with PCI using a new Co-Cr bare metal stent with closed cells design and limited balloon compliance. We considered high-risk features as one of the following: age ≥ 70 years, ejection fraction ≤ 35%, glomerular filtration rate ≤ 60 mL/min, diabetes mellitus, rescue PCI, or chronic atrial fibrillation or other conditions requiring long-term oral anticoagulation therapy. Primary outcome of the study was rate of major adverse cardiac events (MACE) defined as all-cause death, new MI, and target-vessel revascularization. A total of 129 consecutive patients were enrolled (69 ± 11 years, 74% men): 71 (55%) patients with ST-segment elevation MI and 58 (45%) patients with non-ST-segment elevation MI. A total of 153 vessels (169 lesions and 179 stents) were treated. The device success rate was high (98.8%). In-hospital MACE rate was 5.4% mainly because of death associated with the acute MI. At 1-year follow-up, the MACE rate was 17.3%, with 11% all-cause death (7.9% of cardiac origin), 0.6% of stent thrombosis, and 4.6% target-vessel revascularization. CONCLUSIONS: The use of the Co-Cr Presillion stent in patients with high-risk acute MI treated invasively seems to be safe and efficacious with optimal deliverability and good long-term outcomes and represents a good option in the treatment of these patients.

Sport activity in patients with cardiac implantable electronic devices: evidence and perspectives.

Demographic characteristics of patients with cardiac implantable electronic devices have significantly changed during the last few years, according to the ageing of the population and the consequent increase in the number of elderly individuals with indication for pacemaker implant and, on the other hand, to the increased number of young individuals implanted with an implantable cardioverter defibrillator for the primary prevention of sudden death. More and more often, both elderly and young patients ask the physician to deal with the device in their daily activities, which often include sport practice. This latter is advisable because of its recognized benefits on cardiovascular prevention, although there are many limitations for patients with a cardiac implantable electronic device. Hence, the need to balance the patient's request with the appropriate precautions emerging from existing evidence. The current article aims to provide an overview of the most recent data on this topic, derived from registries and observational studies. Over the years an attempt to standardize recommendations has been made, but robust evidence is still lacking. Substantial differences exist between countries based on their sports regulations. Official recommendations of European and American Scientific Societies are resumed. The future perspective is to obtain data to allow these patients a safer practice of sport activity also through technological advances in terms of device materials and programming improvement and the possibility of remote monitoring.