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Objectives: Ascending aorta dilatation in patients with bicuspid aortic valve is related both to genetic and haemodynamic factors. Aim of this study is to compare late progression of ascending aorta dilatation in bicuspid aortic valve patients undergoing surgical aortic valve replacement (SAVR) vs transcatheter aortic valve implantation (TAVI). Methods: Data of 189 consecutive patients who underwent aortic valve replacement for severe bicuspid aortic valve stenosis were prospectively collected. Patients who underwent SAVR were compared to patients who underwent TAVI. Indication to the procedure was validated by the institutional Heart Team. Aortic diameters were evaluated by transthoracic echocardiogram. Differences between preoperative and long-term follow-up ascending aorta diameters were compared in the two groups. Results: Between January 2015 and December 2021, 143(76%) patients underwent SAVR and 46(24%) patients underwent TAVI. At 4.6 (Standard Deviation, SD 1.7) years follow-up, patients in the TAVI group showed significantly lower survival (P = 0.00013) and event-free survival (P < 0.0001). Ascending aorta diameter progression was lower in surgical compared to transcatheter patients, 0.95(0.60,1.30) mm vs 1.65(0.67, 2.63) mm, P = 0.02. Ascending aorta diameter progression indexed for body surface area and height, was lower in the surgical group: 0.72(0.38,1.05) mm/m2 vs 1.05(0.39,1.71) mm/m2 P = 0.02, and 0.59(0.36,0.81) mm/m vs 1.11(0.44,1.78) mm/m, P = 0.001, respectively. At multivariable linear regression analysis transcatheter procedure, baseline aortic diameter, and paravalvular leak were significantly associated with increased postoperative ascending aorta dilatation. Conclusions: Bicuspid aortic valve patients who underwent SAVR, showed significantly less long-term ascending aorta diameter progression than patients who underwent transcatheter procedure.

Aims The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter 1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Methods and results We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HSs). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells when compared with CCS patients (P < 0.0001; P = 0.0101, respectively) and HSs (P = 0.0071; P = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (P = 0.0005 for nuclear vs. cytoplasm localization), while in CCS and HS, it was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared with HS (P = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1-mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the down-regulation of pro-inflammatory cytokine expression. Conclusion NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.

Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways.

Despite the recent innovations in cardiovascular care, atherothrombosis is still a major complication of acute coronary syndromes (ACS). We evaluated the involvement of the CD31 molecule in thrombotic risk through the formation of monocyte-platelet (Mo-Plt) aggregates in patients with ACS with no-ST-segment elevation myocardial infarction (NSTEMI) on top of dual anti-platelet therapy (DAPT). We enrolled 19 control (CTRL) subjects, 46 stable angina (SA), and 86 patients with NSTEMI, of which, 16 with Intact Fibrous Cap (IFC) and 19 with Ruptured Fibrous Cap (RFC) as assessed by the Optical Coherence Tomography (OCT). The expression of CD31 on monocytes and platelets was measured. Following the coronary angiography, 52 NSTEMIs were further stratified according to thrombus grade (TG) evaluation. Finally, a series of ex vivo experiments verified whether the CD31 participates in Mo-Plt aggregate formation. In patients with NSTEMI, CD31 was reduced on monocytes and was increased on platelets, especially in NSTEMI presented with RFC plaques compared to those with IFC lesions, and in patients with high TG compared to those with zero/low TG. Ex vivo experiments documented an increase in Mo-Plt aggregates among NSTEMI, which significantly decreased after the CD31 ligation, particularly in patients with RFC plaques. In NSTEMI, CD31 participates in Mo-Plt aggregate formation in spite of optimal therapy and DAPT, suggesting the existence of alternative thrombotic pathways, as predominantly displayed in patients with RFC.

Acute Coronary Syndromes (ACS) with plaque erosion display dysregulated hyaluronan metabolism, with increased hyaluronidase-2 (HYAL2) expression. However, the expression and the role of this enzyme on platelets has never been explored. We evaluated the platelet’s HYAL2 (pltHYAL2) levels on I) stable angina (SA) and II) ACS patients, furtherly sub-grouped in Intact-Fibrous-Cap (IFC) and Ruptured-Fibrous-Cap (RFC), according to Optical Coherence Tomography. We assessed the HYAL2 role through an in vitro model setting of co-cultured monocytes and platelets, before and after treatment with low-molecular-weight hyaluronic acid (HA) as pro-inflammatory stimulus and with or without HYAL2-antibody to inhibit HYAL2 activity. ACS patients exhibit higher pltHYAL2 levels comparing to SA, with the higher expression for IFC group. The addition of HYAL2-antibody significantly reduced the percentage of monocyte-platelet binding, suggesting that pltHYAL2 enrichment at the site of the culprit lesion is a key mediator in the systemic thrombo-inflammatory status of ACS presenting with plaque erosion.

Aims In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042). Conclusion Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.