Drug-eluting stents are increasingly used to reduce in-stent restenosis and adverse cardiac events after percutaneous coronary interventions. However, the race for the ideal drug-eluting stent is still on, with special regard to the best stent-coating system and the most effective and less toxic drug. Fludarabine, a nucleoside analog, has both anti-inflammatory and antiproliferative cellular effects. The aim of the present study was to assess the cellular and molecular effects of fludarabine on vascular smooth muscle cell (VSMC) growth in vitro and in vivo and the feasibility and efficacy of a fludarabine-eluting stent. To study the biomolecular effects of fludarabine on VSMC proliferation in vitro, rat VSMCs were grown in the presence of 50 microM fludarabine or in the absence of the same. To evaluate the in vivo effect of this drug, male Wistar rats underwent balloon injury of the carotid artery, and fludarabine was locally delivered at the time of injury. Finally, fludarabine-eluting stents were in-laboratory manufactured and tested in a rabbit model of in-stent restenosis. Fludarabine markedly inhibited VSMC proliferation in cell culture. Furthermore, fludarabine reduced neointimal formation after balloon angioplasty in a dose-dependent manner, and fludarabine-eluting stents reduced neointimal hyperplasia by approximately 50%. These in vitro and in vivo cellular effects were specifically associated with the molecular switch-off of signal transducer and activator of transcription (STAT)-1 activation, without affecting other STAT proteins. Fludarabine abolishes VSMC proliferation in vitro and reduces neointimal formation after balloon injury in vivo through specific inhibition of STAT-1 activation. Fludarabine-eluting stents are feasible and effective in reducing in-stent restenosis in rabbits.

cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85alpha (phosphatidylinositol 3-kinase regulatory subunit) is phosphorylated by cAMP/PKA in certain cell lineages, but its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are unknown. In the present study, we evaluated 1) the role of p85alpha in the integration of cAMP/PKA-dependent signaling on the regulation of VSMC and EC growth in vitro; and 2) the effects of PKA-modified p85alpha on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85alpha were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85alpha phosphorylation. Transfected PKA-activated p85alpha binds p21ras, reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85alpha and ERK1/2 inhibition; indeed, PKA-activated p85alpha did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85alpha phosphorylation. Accordingly, PKA-activated p85alpha triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85alpha significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA-activated p85alpha integrates cAMP/PKA signaling differently in VSMCs and ECs. By reducing neointimal hyperplasia without inhibiting endothelial regeneration, it exerts a protective effect against restenosis after balloon injury.

Messenger RNA (mRNA) coronavirus disease of 2019 (COVID-19) vaccines have been recently associated with acute myocarditis, predominantly in healthy young males. Out of 231,989 vaccines administrated in our region (Marche, Italy), we report a case series of six healthy patients (four males and two females, 16.5 years old (Q1, Q3: 15, 18)) that experienced mRNA-COVID-19-vaccines side effects. All patients were hospitalized due to fever and troponins elevation following the second dose of an mRNA-based COVID-19 vaccine. Cardiovascular magnetic resonance (CMR) was performed 72–96 h after vaccination. All patients were treated with colchicine and ibuprofen. Myocarditis was prevalent in males. It was characterized by myocardial edema and late gadolinium enhancement (LGE) in the lateral wall of the left ventricle (LV). One patient showed sole right ventricular involvement, while the females presented with myopericarditis (myocarditis + pericardial effusion). All patients in our series had preserved LV ejection fraction and remained clinically stable during a relatively short inpatient hospital stay. One case presented with atrial tachycardia. At the follow-up, no significant CMR findings were documented after a three-month medical treatment. According to other recently published case series, our report suggests a possible association between acute myocarditis and myopericarditis with mRNA COVID-19 vaccination in healthy young adults and pediatric patients. Not only males are involved, while some arrhythmic manifestations are possible, such as atrial tachycardia. Conversely, we here highlight the benign nature of such complications and the absence of CMR findings after a three-month medical treatment with colchicine and ibuprofen.

AimsWe sought to determine the diagnostic performance, clinical profiles and outcomes of anomalous aortic origin of coronary arteries (AAOCA) using a standardised echocardiographic approach in young adults and athletes.MethodsIn 2015–2019, we screened 5998 outpatients (age 16 years (Q1–Q3: 11, 36)), referred for routine echocardiography, using four specific echocardiographic windows: parasternal short/long axis and apical 4/5-chambers view. Coronary CT confirmed AAOCA. For the performance analysis, 300 coronary-CT scans were available; two independent and double-blinded physicians retrospectively reviewed echocardiographic images.ResultsA total of 47 AAOCA was diagnosed; the overall prevalence was 0.0078%. Over 5 years, we found a significant increment of AAOCA diagnostic rate (P for trend=0.002). Syncope (n=17/47) and palpitations (n=6/47) were prevalent symptoms. All patients suspended sports activity at the diagnosis. Twenty-seven patients underwent surgery, while 20 underwent a conservative medical treatment. All patients are alive at a median follow-up of 3±1.6 years; only surgical repairs restarted their activity. Our method showed better sensitivity than traditional short-axis evaluation: 93% vs 83%, p=0.0030 (AUC 0.96 (95% CI 0.92, 0.99) and AUC 0.89 (95% CI 0.83, 0.95), respectively), with a good interobserver agreement (95%, k=0.83, p<0.001).ConclusionsThe application of a standardised echocardiographic approach for AAOCA detection led to a significantly increased rate of identified anomalies. This approach demonstrated higher sensitivity than the traditional echocardiographic assessment. Implementing this protocol in clinical practice may help improve the AAOCA diagnosis in young adults and athletes.Trial registration numberNCT04224090.